Nanostructures for Antimicrobial Therapy

By Alexandru Mihai Grumezescu

Nanostructures for Antimicrobial Therapy discusses the pros and cons of the use of nanostructured materials in the prevention and eradication of infections, highlighting the efficient microbicidal effect of nanoparticles against antibiotic-resistant pathogens and biofilms.

Conventional antibiotics are becoming ineffective towards microorganisms due to their widespread and often inappropriate use. As a result, the development of antibiotic resistance in microorganisms is increasingly being reported. New approaches are needed to confront the rising issues related to infectious diseases. The merging of biomaterials, such as chitosan, carrageenan, gelatin, poly (lactic-co-glycolic acid) with nanotechnology provides a promising platform for antimicrobial therapy as it provides a controlled way to target cells and induce the desired response without the adverse effects common to many traditional treatments.

Nanoparticles represent one of the most promising therapeutic treatments to the problem caused by infectious micro-organisms resistant to traditional therapies. This volume discusses this promise in detail, and also discusses what challenges the greater use of nanoparticles might pose to medical professionals. The unique physiochemical properties of nanoparticles, combined with their growth inhibitory capacity against microbes has led to the upsurge in the research on nanoparticles as antimicrobials. The importance of bactericidal nanobiomaterials study will likely increase as development of resistant strains of bacteria against most potent antibiotics continues.

• Shows how nanoantibiotics can be used to more effectively treat disease
• Discusses the advantages and issues of a variety of different nanoantibiotics, enabling medics to select which best meets their needs
• Provides a cogent summary of recent developments in this field, allowing readers to quickly familiarize themselves with this topic area

• Language: English
• Publisher: Elsevier Science
• Release date: May 29, 2017
• ISBN: 9780323461511

Book preview

Nanostructures for Antimicrobial Therapy

Nanostructures in Therapeutic Medicine Series

Editors

Anton Ficai

University Politehnica of Bucharest, Bucharest, Romania

Alexandru Mihai Grumezescu

University Politehnica of Bucharest, Bucharest, Romania

Academy of Romanian Scientists, Bucharest, Romania

Table of Contents

Cover image

Title page

Copyright

List of Contributors

Series Foreword

Series Preface

Preface

Chapter 1. Antimicrobials: Meeting the Challenges of Antibiotic Resistance Through Nanotechnology

1. Introduction

2. Current Status of the Menace of Antimicrobial Resistance

3. Antimicrobial Classes and Their Current Effectiveness With Respect to Emerging Drug Resistance

4. Microbial Resistance Mechanism to Antimicrobials

5. Application of Nanotechnology to Counter Antimicrobial Resistance

6. Role of Nanoparticles in Overcoming the Challenge of Antimicrobial Drug Delivery

7. Conclusions

Chapter 2. Nanoantimicrobials: Activity, Benefits, and Weaknesses

1. Introduction

2. Nanoparticles and Nanoformulations

3. Nanoformulations Based on Organic Antibacterial Agents

4. Nanoformulations Based on Inorganic Materials With Antibacterial Activity

5. Antituberculosis-Active Nanoformulations

6. Polymer Matrices With Antimicrobial Activity

7. Risks of Application of Nanoformulations in Therapy

8. Conclusions

Chapter 3. Sensitive and Selective Assay of Antimicrobials on Nanostructured Materials by Electrochemical Techniques

1. Introduction

2. Antimicrobials

3. Electrochemical Techniques

4. Nanostructured Materials

5. Application of Nanostructured Materials in the Determination of Antimicrobials by Electrochemical Techniques

6. Conclusions

List of Abbreviations

Chapter 4. Antimicrobial Polymeric Nanostructures

1. Introduction: Antimicrobial Nanostructures

2. Antibacterial Polymers: Chemical Functionalities and Synthesis

3. Interactions Between Bacteria and Polymeric Materials: Role of the Macromolecular Parameters on Antibacterial Activity

4. Antimicrobial Polymer Nanostructures in Solution

5. Polymer Surfaces With Antimicrobial Activity

6. Summary

Chapter 5. Thin Degradable Coatings for Optimization of Osseointegration Associated With Simultaneous Infection Prophylaxis

1. Introduction to the Arthroplasty Infection Problem and Incidence in Health Care

2. Experimental Section

3. Results and Discussion

4. Conclusions

Chapter 6. Antimicrobial Nanostructures for Neurodegenerative Infections: Present and Future Perspectives

1. Introduction

2. Relationship of Microbes in Neuroinfection-Assisted Neurodegeneration

3. Possible Approach Using Nanoparticles for the Treatment of Infectious Disease

4. Properties of Nanostructured Nanoparticles

5. Nanostructured Nanoparticles in Biomedical Research

6. Principle of Nanoparticle Entry Into Cellular System

7. Application of Nanostructured Nanoparticles in Pharmaceutical Science

8. Neuroinfection-Associated Neurodegenerative Disease

9. The Mechanistic Approach of Nanomedicine for Neuroinfectious Neurodegenerative Disease

10. Toxicological Hazards of Nanoparticles

11. Nanotoxicology

12. Challenge to Usage and Management of Nanoparticles

13. Future Perspectives

14. Conclusions

Chapter 7. Nanocarriers and Their Potential Application as Antimicrobial Drug Delivery

1. Introduction

2. Liposomes

3. Polymeric Nanoparticles

4. Solid Lipid Nanoparticles

5. Dendrimers

6. Antimicrobial Activity of the Metal Oxide Nanoparticles

7. Conclusion

Chapter 8. Delivery of Antimicrobials by Chitosan-Composed Therapeutic Nanostructures

1. Introduction

2. Antimicrobial Peptides: A New Addition to the Therapeutic Arsenal

3. Chitosan as a Recognized Biopolymer in the Development of Therapeutic Nanostructures

4. Chitosan Nanocarriers

5. Advances in the Development of Chitosan-Based Nanocarriers for Antimicrobial Peptide Delivery

6. Conclusions

Chapter 9. Antimicrobial Thin Coatings Prepared by Laser Processing

1. Introduction

2. Nanostructured Thin Coatings With Antimicrobial Properties

3. Ion Implantation in Thin Coatings

4. Antifouling and Antiadherent Thin Coatings

5. Composite Thin Coatings as Drug Delivery Systems for Antibiotics and Phytochemicals

6. Biomimetic Thin Coatings With Antibacterial Properties

7. Antimicrobial Peptide-Modified Thin Coatings

8. Other Examples of Laser-Modified Thin Coatings for Antibacterial Applications

9. Conclusions

Chapter 10. Antimicrobial Photodynamic Therapy With Nanoparticles Versus Conventional Photosensitizer in Oral Diseases

1. Introduction

2. Antimicrobial Concepts of Photodynamic Therapy

3. Characteristics and Types of Photosensitizers

4. Photodynamic Therapy Advantages

5. Photodynamic Therapy Limitations

6. Applications of Photodynamic Therapy in Oral Microbial Diseases

7. Nanotechnology in Photodynamic Therapy

8. Conclusion

Chapter 11. Applications of ¹⁹F Magnetic Resonance Spectroscopy and Imaging for the Study of Nanostructures Used in Antimicrobial Therapy

1. Introduction

2. Introduction to Antimicrobial Therapy and Biology of Bacteria

3. Diagnostic and Therapeutic Applications of ¹⁹F Magnetic Resonance Spectroscopy and ¹⁹F Magnetic Resonance Imaging Techniques to Nanomedicine in Antimicrobial Therapy

4. Fluorine-Containing Compounds Synthesized by the Use of Bacteria

5. Study of Nanostructures Used in Antimicrobial Therapy

6. Conclusions

Chapter 12. Essential Oils and Nanoparticles: New Strategy to Prevent Microbial Biofilms

1. Introduction

2. Microbial Biofilms at a Glance

3. Essential Oils With Antimicrobial/Antibiofilm Activity

4. Carbon Nanotubes

5. Conclusions

Chapter 13. Nanocarrier-Assisted Antimicrobial Therapy Against Intracellular Pathogens

1. Introduction

2. Targeting Strategies to Treat Intracellular Infections

3. Characteristics of an Ideal Nanocarrier for Intracellular Drug Delivery

4. Intracellular Delivery Performances of Different Nanocarriers for Effective Eradication of Various Infectious Diseases

5. Conclusions

Chapter 14. Preparation and Antimicrobial Activity of Inorganic Nanoparticles: Promising Solutions to Fight Antibiotic Resistance

1. Introduction

2. Silver Nanoparticles

3. Gold Nanoparticles

4. Zinc Oxide Nanoparticles

5. Magnetite Nanoparticles

6. Copper Oxide Nanoparticles

7. Conclusions

Chapter 15. Outer Membrane Vesicles of Gram-Negative Bacteria: Nanoware for Combat Against Microbes and Macrobes

1. Introduction

2. Structure and Biogenesis of OMVs

3. Variablity and Regulation of OMVs

4. OMVs as Combat Nanoware

5. Conclusions and Future Projections

Chapter 16. Organic Nanocarriers for the Delivery of Antiinfective Agents

1. Introduction

2. Drug Delivery to the Tooth and Oral Mucosa

3. Nanoparticulate Drug Delivery Systems for Use in Oral Mucosal Infections

4. Nanoparticulate Drug Delivery Systems for Use in Dental Caries

5. Nanoparticulate Drug Delivery Systems for Use in Periodontal Disease

6. Nanoparticulate Drug Delivery Systems for Use in Antimicrobial Photodynamic Therapy

7. Conclusions and Future Perspectives

Chapter 17. Nanocarriers for Plant-Derived Natural Compounds

1. Introduction

2. Properties of Polyphenols

3. Nanoencapsulation Techniques

4. Methods for the Preparation of Carriers

5. Conclusions

Chapter 18. Fullerene Derivatives in Photodynamic Inactivation of Microorganisms

1. Fullerenes as Nanomaterials With Biological Applications

2. Photodynamic Inactivation of Microorganisms

3. Fullerene Structures for Applications in Photodynamic Inactivation

4. Absorption and Fluorescence Spectroscopic Properties of Fullerenes

5. Photodynamic Activity of Fullerenes

6. Fullerenes for Antimicrobial Photoinactivation

7. Mechanism of Action Mediated by Fullerenes

8. Fullerenes for In Vivo Antimicrobial Photoinactivation

9. Conclusions

Chapter 19. Silver Iodide Nanoparticles as an Antibiofilm Agent—A Case Study on Gram-Negative Biofilm-Forming Bacteria

1. Introduction to Biofilm

2. Biofilm-Forming Bacteria

3. Biofilm Formation in Biomedical Devices

4. Effect of Antibiotics in Biofilm-Forming Bacteria

5. Effect of Nanoparticles in Biofilm-Forming Bacteria

6. Synthesis of Silver Iodide Nanoparticles

7. Effect of Silver Iodide Nanoparticles on Bacterial Biofilm

8. Conclusions

Chapter 20. Nanoformulations for the Therapy of Pulmonary Infections

1. Introduction

2. Pulmonary Infections, General Therapy, and Nanoformulations

3. Conclusions

List of Abbreviations

Chapter 21. Nanocarriers for Photosensitizers for Use in Antimicrobial Photodynamic Therapy

1. Introduction

2. Antimicrobial Photodynamic Therapy

3. Use of Nanotechnology in aPDT

4. Conclusions, Critical Review, and Future Perspectives

Chapter 22. Zinc Oxide Nanostrucures: New Trends in Antimicrobial Therapy

1. Introduction

2. Properties of Zinc Oxide Nanoparticles

3. Methods of Synthesis

4. Applications of Zinc Oxide Nanoparticles

5. Antimicrobial Zinc Oxide Nanoparticles

6. Mechanism of Antimicrobial Activity

7. Zinc Oxide Thin Films, Coatings, and Composites

8. Conclusions

Chapter 23. Copper-Based Nanoparticles as Antimicrobials

1. Introduction

2. Antibacterial Activity of CuO NPs

3. Antibacterial Activity of Cu2O NPs

4. Cu/Polymer and Cu/Cu2O Composite NPs

5. Antifungal Activity of Cu-Based NPs

6. Conclusions

Chapter 24. Antimicrobial Applications of Superparamagnetic Iron Oxide Nanoparticles: Perspectives and Challenges

1. Why Are Superparamagnetic Iron Oxide Nanoparticles So Unique?

2. Applications of Antimicrobial SPIONs Against Bacteria and Fungi

3. SPIONs/Silver Nanoparticles as Powerful Antimicrobial Agents

4. Can SPIONs Promote Bacteria Biofilm Disruption?

5. SPIONs and Infectious Parasitic Diseases: Nanodiagnosis, Nanovaccines, and New Therapeutic Strategies

6. Mechanisms of SPION Antimicrobial Activity

7. Challenges and Perspectives in the Design of Antimicrobial SPIONs

Chapter 25. Silica Nanoparticles as a Basis for Efficacy of Antimicrobial Drugs

1. Introduction

2. Structural Characterization of Silica-Loaded Antibiotics

3. In Vitro Susceptibility of Silica-Loaded Antibiotics

4. In Vivo Susceptibility of Silica-Loaded Antibiotics

5. In Vivo Efficiency of Therapy of Septic Mice by Combination of Two Antibiotics

6. In Vivo Susceptibility of Composition of Silica-Loaded NaCl and Antibiotics

7. In Vivo Susceptibility of Silica-Loaded Antibiotics in Candidiasis

8. In Vivo Susceptibility of Silica-Loaded Antibiotics in Disseminated Tuberculosis

9. In Vitro Effects of Silica-Loaded Antibiotics at Macrophage Functions

10. Efficacy of Silica-Loaded Fosfomycin in Cut or Burn Wounds Healing

11. Clinical Efficiency of Silica-Loaded Ceftriaxone

12. Discussion

13. Conclusions

Chapter 26. Silver Nanoparticles as Antimicrobial Agents: Past, Present, and Future

1. Introduction

2. Ancient Uses of Colloidal Silver Nanoparticles

3. Chemical, Physical, or Biological Syntheses of Silver Nanoparticles: A Complex Question

4. Fine-Tuning the Synthesis and Characteristics of Silver Nanoparticles

5. Antimicrobial Effects of Silver Nanoparticles: Promiscuity or Selectivity?

6. Nonantimicrobial Biological Effects of Silver Nanoparticles

7. Mechanisms of Action Underlying Antimicrobial Effects of Silver Nanoparticles

8. Mathematical and Computational Tools Applied to Silver Nanoparticles

9. Current Products Containing Silver Nanoparticles

10. Avoiding, Minimizing, and Mitigating the Possible Adverse Impacts of Silver Nanoparticles

11. Regulatory and Risk Management Concerning the Use of Silver Nanoparticles

12. Conclusions

Chapter 27. Encapsulation of Lethal, Functional, and Therapeutic Medicinal Nanoparticles and Quantum Dots for the Improved Diagnosis and Treatment of Infection

1. Introduction

2. Survey of Nanoactives

3. Uses of the Technology

4. Evaluation of Scope

5. The Future and Opportunities

6. Conclusions and Summary

Chapter 28. Advanced Nanocomposites With Noble Metal Antimicrobial Nanoparticles: How to Design a Balance Among Antimicrobial Activity, Bioactivity, and Safe Delivery to the Place of Infection

1. Antimicrobials: Historical Overview

2. Challenges for the Use of Nanotechnology Against Infections

3. Inorganic Antimicrobial Materials

4. Physicochemical Properties of Noble Metals

5. Medical Applications of Noble Metals

6. Antibacterial Activity of Noble Metals

7. Toxicity of Noble Metals

8. Perspectives and Concluding Remarks

Chapter 29. Clinical Developments in Antimicrobial Nanomedicine: Toward Novel Solutions

1. Introduction

2. Understanding Clinical Trials

3. Overview of Antimicrobial Nanomedicine Clinical Trials

4. Nanoparticles Used

5. Individual Studies Analysis

6. Final Considerations

Chapter 30. Recent Citation Classics in Antimicrobial Nanobiomaterials

1. Overview

2. Recent Citation Classics in Antimicrobial Nanoparticles

3. Conclusion

Index

Copyright

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List of Contributors

David Aebisher

University of Rzeszów, Rzeszów, Poland

Shorter University, Rome, GA, United States

Nelson V. Alfredo,     Instituto de Ciencia y Tecnología de Polímeros (ICTP), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

Ecaterina Andronescu,     University Politehnica of Bucharest, Bucharest, Romania

Andrei I. Apostol,     Horia Hulubei National Institute for Physics and Nuclear Engineering, Magurele, Romania

Irina Arhire,     University of Stuttgart, Stuttgart, Germany

Nurgul K. Bakirhan,     Ankara University, Ankara, Turkey

Dorota Bartusik

University of Rzeszów, Rzeszów, Poland

Southern Polytechnic State University, Marietta, GA, United States

Oguz Bayraktar,     Ege University, Izmir, Turkey

Anke Bernstein,     Albert-Ludwigs-University of Freiburg, Freiburg, Germany

Marcelo P. Bernuci,     University Center of Maringa, Maringa, Brazil

Marius Boboc,     University Politehnica of Bucharest, Bucharest, Romania

Cínthia C. Bonatto

Embrapa Genetic Resources and Biotechnology, Brasília, Brazil

University of Brasilia, Brasília, Brazil

TecSinapse, São Paulo, Brazil

Mariza Bortolanza,     University of São Paulo, Ribeirao Preto, Brazil

Asuman Bozkır,     Ankara University, Ankara, Turkey

Sophie Burtscher,     Albert-Ludwigs-University of Freiburg, Freiburg, Germany

Mariana C. Chifiriuc

University of Bucharest, Bucharest, Romania

Research Institute of the University of Bucharest, Bucharest, Romania

Manasi Chogale,     Institute of Chemical Technology, Mumbai, India

Beata Chudzik-Rząd,     Medical University of Lublin, Lublin, Poland

Filis Curti,     University Politehnica of Bucharest, Bucharest, Romania

Carmen Curutiu,     Research Institute of the University of Bucharest (ICUB), Bucharest, Romania

Bhaskar Das,     Indian Institute of Technology Guwahati, Guwahati, India

Elaine Del-Bel,     University of São Paulo, Ribeirao Preto, Brazil

Catherine Dendrinou-Samara,     Aristotle University of Thessaloniki, Thessaloniki, Greece

Burcu Devrim,     Ankara University, Ankara, Turkey

Baskaran Dheeba,     SASTRA University, Kumbakonam, India

Sagar Dhoble,     Institute of Chemical Technology, Mumbai, India

Gennaro A. Dichello,     The University of Brighton, Brighton, United Kingdom

Edgardo N. Durantini,     Universidad Nacional de Río Cuarto, Río Cuarto, Argentina

Alexander Dushkin,     Institute of Solid State Chemistry and Mechanochemistry, Novosibirsk, Russia

İpek Erdoğan,     Izmir Institute of Technology, Izmir, Turkey

Reza Fekrazad

AJA University of Medical Sciences, Tehran, Iran

Universal Scientific Education and Research Network (USERN), Tehran, Iran

Anton Ficai,     University Politehnica of Bucharest, Bucharest, Romania

Amalia M. Fleacă,     University Politehnica of Bucharest, Bucharest, Romania

Oana Fufa

University Politehnica of Bucharest, Bucharest, Romania

National Institute for Laser, Plasma and Radiation Physics, Magurele, Romania

Rainer Gadow,     University of Stuttgart, Stuttgart, Germany

Konstantin Gaidul,     Scientific Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia

Vinod Ghodake,     Institute of Chemical Technology, Mumbai, India

Kleoniki Giannousi,     Aristotle University of Thessaloniki, Thessaloniki, Greece

Irina Goldina,     Scientific Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia

Alexandru Mihai Grumezescu,     University Politehnica of Bucharest, Bucharest, Romania

Paula S. Haddad,     Federal University of São Paulo (UNIFESP), São Paulo, Brazil

Gabriel H. Hawthorne,     University Center of Maringa, Maringa, Brazil

Alina M. Holban,     University of Bucharest, Bucharest, Romania

Ana C. Issy,     University of São Paulo, Ribeirao Preto, Brazil

Josef Jampílek,     Comenius University, Bratislava, Slovakia

Mădălina L. Jianu,     University Politehnica of Bucharest, Bucharest, Romania

Katayoun A.M. Kalhori,     Iranian Medical Laser Association, Tehran, Iran

Gülcan Kalmaz,     Ege University, Izmir, Turkey

Crina Kamerzan

Research Institute of the University of Bucharest, Bucharest, Romania

S.C. Sanimed International IMPEX SRL., Calugareni, Romania

Marikani Kannan,     V.H.N.S.N. College, Virudhunagar, India

Jaspreet Kaur,     Akal College of Pharmacy and Technical Education, Sangrur, India

Anderas Killinger,     University of Stuttgart, Stuttgart, Germany

Vladimir Konenkov,     Scientific Institute of Clinical and Experimental Lymphology, Novosibirsk, Russia

Ozcan Konur,     Yildirim Beyazit University, Ankara, Turkey

Merve D. Köse,     Ege University, Izmir, Turkey

Vladimir Kozlov,     Scientific Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia

Katarína Král'ová,     Comenius University, Bratislava, Slovakia

Peter Krieg,     University of Stuttgart, Stuttgart, Germany

Lalit Kumar

Shivalik College of Pharmacy, Nangal, India

I.K. Gujral Punjab Technical University, Jalandhar, India

Veronica Lazar

University of Bucharest, Bucharest, Romania

Research Institute of the University of Bucharest, Bucharest, Romania

Iulia I. Lungu,     University Politehnica of Bucharest, Bucharest, Romania

Nikolai Lyakhov,     Institute of Solid State Chemistry and Mechanochemistry, Novosibirsk, Russia

Alexander Lykov,     Scientific Institute of Clinical and Experimental Lymphology, Novosibirsk, Russia

Ayyan Maniraj,     V.H.N.S.N. College, Virudhunagar, India

Hermann O. Mayr,     Albert-Ludwigs-University of Freiburg, Freiburg, Germany

Neelesh K. Mehra,     Texas A & M University, Kingsville, TX, United States

María E. Milanesio,     Universidad Nacional de Río Cuarto, Río Cuarto, Argentina

Paulo V. Milreu,     TecSinapse, São Paulo, Brazil

Arunachalam Muthuraman

Akal College of Pharmacy and Technical Education, Sangrur, India

JSS University, Mysuru, Karnataka, India

AmirHossein Nejat,     Louisiana State University, New Orleans, LA, United States

Sibel A. Ozkan,     Ankara University, Ankara, Turkey

Anastasia Pantazaki,     Aristotle University of Thessaloniki, Thessaloniki, Greece

Sanjukta Patra,     Indian Institute of Technology Guwahati, Guwahati, India

Vandana Patravale,     Institute of Chemical Technology, Mumbai, India

Milena T. Pelegrino,     Federal University of ABC (UFABC), São Paulo, Brazil

Andrzej Polski,     Medical University of Lublin, Lublin, Poland

Roxana-Cristina Popescu

University Politehnica of Bucharest, Bucharest, Romania

Horia Hulubei National Institute for Physics and Nuclear Engineering, Magurele, Romania

Daniel Popescu,     University of Craiova, Craiova, Romania

Kaniappan Rajarathinam,     V.H.N.S.N. College, Virudhunagar, India

Ivy G. Reis

Embrapa Genetic Resources and Biotechnology, Brasília, Brazil

University of Brasilia, Brasília, Brazil

TecSinapse, São Paulo, Brazil

Juan Rodríguez-Hernández,     Instituto de Ciencia y Tecnología de Polímeros (ICTP), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

Ana-Maria Roşu,     University Politehnica of Bucharest, Bucharest, Romania

Antonello Santini,     University of Napoli Federico II, Napoli, Italy

Dipak K. Sarker,     The University of Brighton, Brighton, United Kingdom

Amedea B. Seabra,     Federal University of ABC (UFABC), São Paulo, Brazil

Luciano P. Silva

Embrapa Genetic Resources and Biotechnology, Brasília, Brazil

University of Brasilia, Brasília, Brazil

Ariane P. Silveira

Embrapa Genetic Resources and Biotechnology, Brasília, Brazil

University of Brasilia, Brasília, Brazil

Jan Sobczyński,     Medical University of Lublin, Lublin, Poland

Eliana B. Souto

University of Coimbra, Coimbra, Portugal

REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

Mariana B. Spesia,     Universidad Nacional de Río Cuarto, Río Cuarto, Argentina

Norbert Suedkamp,     Albert-Ludwigs-University of Freiburg, Freiburg, Germany

Maria do Céu Teixeira,     University of Coimbra, Coimbra, Portugal

Bengi Uslu,     Ankara University, Ankara, Turkey

Bhuvaneshwar Vaidya,     Keck Graduate Institute, Claremont, CA, United States

Srinivasan Venkatesan,     Periyar University, Salem, India

Shivani Verma

I.K. Gujral Punjab Technical University, Jalandhar, India

Rayat Bahra College of Pharmacy, Hoshiarpur, India

Marija Vukomanović,     Jožef Stefan Institute, Ljubljana, Slovenia

Rakesh C. YashRoy,     ICAR—Indian Veterinary Research Institute, Bareilly, India

Series Foreword

Material science and engineering at the nanoscale have brought revolutionary advances to the biomedical sciences, overturning many of the known traditional approaches. Nanotechnology has driven many of the most successful innovative technologies, and their impressive record of accomplishment has made nanostructures promising candidates for future therapy. The advantages that nanomaterials have already provided to therapeutics, such as targeted and controlled delivery, wide accessibility, high specificity, low side effects, improved efficiency, and impressive versatility, are currently considered key elements in designing personalized medicine approaches for prophylaxis, diagnosis, and therapy.

Therapeutic nanostructures can be highly diverse, and their unique properties have led to the development of highly specialized biosensors, more efficient drug delivery vehicles, and controlled release targeting systems to fight severe or incurable diseases, such as cancer, infections, and cardiovascular disease.

In view of the progress made in the field of therapeutic nanotechnology, and its rapidly progressing expansion, this book aims to collect together in one place all the most recent and innovative aspects regarding the impact of nanomaterials in both current and future therapy. The book is organized in five volumes, covering the main areas that are relevant for the design and implementation of nanostructures in medical therapies.

The first volume, Nanostructures for Novel Therapy: Synthesis, Characterization and Applications, describes methods to obtain and characterize nanosystems, emphasizing their biomedical applications. Special attention in this volume is paid to modern synthesis methods to reduce side effects and limit the toxicity of nanomaterials in biomedical applications. Numerous examples of nanostructures designed for therapy, as well as the most efficient synthesis and characterization routes for these materials, are clearly described and critically analyzed.

The second volume, entitled Nanostructures for Drug Delivery, covers one of the most widely utilized and investigated applications of nanomaterials in the biomedical field, namely, drug delivery. The design of nanoscale agents to specifically and safely carry therapeutic agents to their final destination is an intriguing approach to future targeted therapeutics. This approach could provide a treatment for previously incurable diseases, as well as reducing the side effects of current drugs. Many highly active drugs are severely limited by side effects related to their unspecific sites of action. This book introduces readers to the amazing field of nanomedicine by discussing the versatility and variety of nanovehicles for drug delivery and targeting. Moreover, readers will find numerous examples, and will learn about the currently used or investigational drug delivery agents for therapy, prophylaxis and diagnosis.

Volume 3, Nanostructures for Antimicrobial Therapy, highlights the impressive progress made by nanotechnology in the design of novel antimicrobial approaches. Since microbial resistance to antibiotics is a very real and worrying issue growing throughout the world, the development of more efficient antimicrobial agents has a high priority to allow control of infections in the future. Antimicrobial nanosystems have proved to be highly efficient against drug-resistant microorganisms, and are able to fight biofilm-associated infections and control the social behavior of microbial communities. Nanostructures can also reduce microbial virulence factors and reduce pathogenesis mechanisms, thus offering a promising alternative for future therapy.

Volume 4, entitled Nanostructures for Cancer Therapy, covers the applications of nanomedicine in cancer diagnosis and treatment. The use of nanoparticles for cancer therapy is not in itself a new approach, but numerous advances have been recently made in this area, and the aim of this book is to cover the most interesting new approaches in the management of this deadly disease. Nanosized drugs are currently believed to represent the most efficient approach in cancer chemotherapy, and this volume provides coverage of the latest novel findings, while also discussing possible improvements in more established types of nanosystems to increase the efficiency of cancer therapy.

Last but not least, Volume 5 of this series, entitled Nanostructures for Oral Medicine, covers the progress made in applications of nanotechnology in treating various diseases of the oral cavity and in dentistry. Readers will have the chance to learn about the most efficient modern materials used to treat or prevent widely encountered oral diseases, such as gingivitis, periodontitis, caries, and dental plaque. Moreover, restorative dentistry now makes wide use of nanomaterials.

Overall, this book series will provide a state-of-the-art compendium of knowledge and a crystal ball to see into the future of biomedical nanotechnology and nanomedicine. It will appeal to researchers, clinicians, engineers, pharmacologists, pharmacists, oncologists, infectious disease experts, and dentists. Furthermore, interested general readers may discover the impact, current progress, and future applications of nanotechnology in therapeutics and diagnosis. Taken together, nanoscale approaches will improve the efficiency of personalized medicine for better management of diseases in the 21st century.

Michael R. Hamblin,     Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, United States,     Department of Dermatology, Harvard Medical School, Boston, MA, United States,     Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, United States

Series Preface

In our permanently changing world, novel therapeutic strategies are constantly required to manage the health and wellbeing of the population. Although numerous diseases are currently considered incurable, massive progress made in biomedicine, but also associated fields, such as chemistry, physics, engineering, pharmacology, and materials science, offers a new solution to the therapeutics domain. In this context, most physicists and researchers believe that a personalized and adequate treatment may significantly improve the outcome of severe diseases and ensure faster healing. Nanotechnology offers great perspectives for personalized medicine; nanostructures proved their efficiency, versatility, and sensibility in therapy, prophylaxis, and diagnosis. The dynamic field of nanosized materials has numerous applications in the biomedical field, especially in therapy. This series of five volumes emerged from the need to learn about recent progress in the science of nanostructured materials to improve current therapy and lead to the next level. The books offer an interesting and updated perspective regarding applications of nanomaterials in therapy of most investigated and difficult-to-treat diseases, such as cancer and severe infections. The presentation style of each chapter contained in those five volumes is clear and easy to understand both by specialized and unspecialized readers and is interesting for biomedical doctors, researchers, and engineers. The series is organized in an attractive manner for students and academics in the field, starting with a volume dealing with synthesis, characterization, and main applications of nanostructures, emphasizing their impact in therapy. The next volume reveals the most recent progress made in a much investigated field, considered a key element in personalized medicine and future therapy, namely, nanostructured drug delivery systems. Their impact in antimicrobial therapy is also widely discussed and suggestive examples are given and explained. Moreover, a whole volume is dedicated to the management of the disease of the century—cancer—revealing the huge value added by the utilization of nanosystems in the therapy of this deadly disease. Important aspects related to improved diagnosis and prophylaxis are highlighted. In the last volume, the progress and novel applications of nanotechnology in oral medicine are dissected. The field of oral diseases represents a wide interest and a priority field since both physicists and researchers believe that they can be prevented and treated more easily with targeting systems and nanofunctional prosthetics. All chapters are clearly illustrated to highlight important or more difficult-to-understand aspects, and suggestive examples are often enumerated in organized tables, which are explained and discussed. Overall, the series contains very recent but accessible information regarding the progress of nanostructures in therapeutics and gives a novel perspective on the future therapy of severe diseases.

Alexandru Mihai Grumezescu,     University Politehnica of Bucharest, Bucharest, Romania,     Academy of Romanian Scientists, Bucharest, Romania

Preface

Volume 3 of the series Therapeutic Nanostructures is entitled Nanostructures for Antimicrobial Therapy. In this volume recent information regarding different types of nanostructured antimicrobial agents, their fabrication, and main properties are revealed. The main focus of the volume is to discuss the most frequent problems caused by resistant microorganisms and difficult-to-treat bacteria and to highlight the impact of recently developed antimicrobial nanosystems. Various methods to obtain efficient nanomaterials with antimicrobial properties are described. Moreover, their advantages, challenges, and main applications are revealed in the chapters of this volume. The design of targeting antimicrobial therapeutics able to specifically detect pathogenic microorganisms and to act in a very specific manner still represents a much investigated concept. Although numerous approaches were developed to control severe infections, the ability of microbes to adapt and select resistance still represents a major challenge in the design of alternative antimicrobial agents. This volume also presents the progress made in the design of nanostructured drugs containing natural antimicrobials, which are considered more effective in limiting the selection of resistant mutants, as compared to classical antibiotics, and are regarded as environmentally safe. Nonetheless, the progress made in the case of particularly difficult-to-reach infections, such as intracellular pathogens and biofilm-associated infections, is separately discussed, innovation made in the detection and therapy by using nanoscale materials being highlighted. Volume 3 contains 30 chapters, prepared by outstanding international researchers from the United States, Argentina, Italy, Poland, Romania, Russia, Turkey, Iran, India, Czech Republic, Slovakia, Spain, Germany, Portugal, Greece, Brazil, the United Kingdom, and Slovenia.

In Chapter 1, entitled Antimicrobials: Meeting Challenges of Antibiotic Resistance Through Nanotechnology, Bhaskar Das et al. highlight the current advances underlying emergence of antibiotic-resistant pathogens and endorse the use of nanomaterials to counteract antimicrobial resistance and delivery of antimicrobial drugs.

Chapter 2, prepared by Josef Jampílek, entitled Nanoantimicrobials: Activity, Benefits, and Weaknesses, focuses on the methods of incorporation of active ingredients into different types of nanocarriers for targeted biodistribution/controlled release, discussing the antimicrobial effectiveness of these formulations. In addition, weaknesses of the application of nanoantimicrobials in clinical practice and potential health risks related to the application of nanoformulations are discussed.

Chapter 3, written by Nurgul K. Bakirhan et al., entitled Sensitive and Selective Assay of Antimicrobials on Nanostructured Materials by Electrochemical Techniques, presents an up-to-date overview of the classification of nanoantimicrobial agents and their used fields, nanostructured material types applied for a specific infection, and applications in the determination of antimicrobials (on nanostructured materials) by sensitive and selective electrochemical techniques.

In Chapter 4, entitled Antimicrobial Polymeric Nanostructures, Nelson Vargas Alfredo et al. discuss alternative strategies to prepare nanostructured antimicrobial polymeric materials. Also the authors review the generation of materials exhibiting nanostructured interfaces that reduce or prevent the adhesion of microorganisms.

Chapter 5, entitled Thin Degradable Coatings for Optimization of Osteointegration Associated With Simultaneous Infection Prophylaxis and prepared by Anke Bernstein et al., presents novel approaches related to prevention of prosthetic joint infection. Both antibiotic prophylaxis and faster osteointegration can be obtained by the incorporation of bactericidal active metals in degradable calcium and phosphorus-containing coatings.

Chapter 6, entitled Nanostructure and Nanomedicine of Antimicrobial Agents for Neuroinfections of Neurodegenerative Diseases: Current and Future Perspectives, prepared by Arunachalam Muthuraman et al., gives an overview of the mechanisms involved in the antimicrobial activity of nanomaterials, i.e., (1) destruction of peptidoglycan layer; (2) release of toxic metal ions; (3) alteration of cellular pH via proton efflux pumps; (4) generation of reactive oxygen species; (5) damage of nuclear materials; and (6) loss of ATP production. Also, this chapter focuses on the current perspectives of nanostructures and nanomedicine in the development if improved antimicrobial agents for the possible management of infection-associated neurodegenerative disorders.

Burcu Devrim and Asuman Bozkir in Chapter 7, entitled Nanocarriers and Their Potential Application as Antimicrobial Drug Delivery, focus on the properties of various nanocarriers including liposomes, solid lipid nanoparticles, polymeric nanoparticles, dendrimers, and metal nanoparticles as promising tools for antimicrobial drugs. The potential application of these nanoparticles in the management of infections is also reviewed.

Teixeira M.C. et al. in Chapter 8, Delivery of Antimicrobials by Chitosan-Composed Therapeutic Nanostructures, review the current progress of theoretical concepts and current advances related to the development of chitosan-based nanostructures for antimicrobial peptides delivery.

Roxana-Cristina Popescu et al. in Chapter 9, Antimicrobial Thin Coatings Prepared by Laser Processing, review some recent examples of antimicrobial coatings obtained using laser processing, focusing on pulsed laser deposition and matrix-assisted pulsed laser deposition. The ion implantation approach is also discussed, as it is becoming increasingly used in the modification of implants and medical device surfaces to obtain improved antimicrobial properties.

Reza Fekrazad et al. in Chapter 10, entitled Antimicrobial Photodynamic Therapy With Nanoparticle Versus Conventional Photosensitizer in Oral Diseases, discuss the advantages and disadvantages of conventional photodynamic therapy by means of chemical photosensitizers compared to nanoparticle-based photodynamic therapy in the management of oral microbial diseases.

Chapter 11, prepared by Dorota Bartusik, entitled Applications of ¹⁹F Magnetic Resonance Spectroscopy and Imaging for the Study of Nanostructures Used in Antimicrobial Therapy, summarizes diagnostic and therapeutic applications of ¹⁹F magnetic resonance spectroscopy and ¹⁹F magnetic resonance imaging techniques to nanomedicine in antimicrobial therapy. The authors provide an overview of the known examples of the synthesis of fluorine-containing compounds by the use of bacteria species and their analysis by ¹⁹F nanomagnetic resonance.

Chapter 12, prepared by Mariana Carmen Chifiriuc et al., entitled Essential Oils and Nanoparticles: New Strategy to Prevent Microbial Biofilms, gives an up-to-date overview of the aspects related to the manufacturing, characterization, and antibiofilm activity of essential oils–loaded nanoparticles, highlighting aspects of the organo-inorganic and bioorganic nanostructured systems based on essential oils with antibiofilm activity.

Chapter 13, entitled Nanocarrier-Assisted Antimicrobial Therapy Against Intracellular Pathogens, prepared by Lalit Kumar et al., gives an overview of the impact of intracellular pathogens against human health, problems in the eradication of intracellular infection, and different nanocarrier systems being used to deliver antimicrobial agents for targeted eradication of intracellular pathogens.

Chapter 14, Preparation and Antimicrobial Activity of Inorganic Nanoparticles: Promising Solutions to Fight Antibiotic Resistance, prepared by Marius Boboc et al., is focused on applications and properties of inorganic nanostructured materials and discusses the main advantages and risks of using different metal and metal oxide nanoparticles, such as silver nanoparticles, gold nanoparticles, zinc oxide nanoparticles, magnetite nanoparticles, and copper oxide nanoparticles as antimicrobial agents.

Chapter 15, prepared by Rakesh Chander YashRoy, entitled Outer Membrane Vesicles of Gram-Negative Bacteria: Nanoware for Combat Against Microbes and Macrobes, focuses on the outer membrane vesicles (OMVs) produced exclusively by Gram-negative organisms. OMVs contain hydrolytic enzymes for breaking down lipid, peptidoglycan, and proteins, thereby enabling bacteria to lyse competing microbes and digest and absorb food reserves available nearby. OMVs are so versatile that bacteria deploy them as combat arsenal for their survival and spread. Isolated OMVs are also being pitted for use as organism-free vaccines in nanosize.

Jan Sobczyński et al. in Chapter 16, entitled Organic Nanocarriers for the Delivery of Antiinfective Agents, present the requirements for nanoparticulated dental delivery systems and the advantages of various delivery strategies for enhanced efficiency for particular infections.

Oguz Bayraktar et al. in Chapter 17, Nanocarriers for Plant-Derived Natural Compounds, discuss nanoencapsulation methods and advances in carrier systems for plant-derived natural compounds.

Chapter 18, entitled Fullerene Derivatives in Photodynamic Inactivation of Microorganisms, prepared by Mariana B. Spesia et al., presents novel approaches related to cationic molecular architectures bearing fullerene C60 that are interesting photosensitizers with potential applications in photodynamic inactivation of microorganisms. Also fullerenes combined with tetrapyrrolic macrocycles represent attractive molecular structures to form permanent antimicrobial surfaces activated by visible light.

M. Kannan et al. in Chapter 19, entitled Silver Iodide Nanoparticles as an Antibiofilm Agent—A Case Study on Gram-Negative Biofilm-Forming Bacteria, highlight the inhibitory properties of biosynthesized AgI nanoparticles to modulate biofilm-related infections.

Chapter 20, Nanoformulations for the Therapy of Pulmonary Infections, prepared by Sagar Dhoble et al., reports the current status of the various microbial infections afflicting the respiratory system followed by an overview of the formulations for the therapy of the same with special emphasis on the use of biomedical nanostructures.

Jan Sobczyński et al. in Chapter 21, entitled Nanocarriers for Photosensitizers for Use in Antimicrobial Photodynamic Therapy, present the advantages of various nanoscale delivery systems for the design of photosensitizers and also review different delivery strategies.

Chapter 22, prepared by Iulia Ioana Lungu, entitled Zinc Oxide Nanostrucures: New Trends in Antimicrobial Therapy, reveals the main synthesis routes to offer particular properties to biomedical ZnO nanoparticles and how they can be modulated to obtain suitable agents for therapy, prophylaxis, and management of various diseases, highlighting the progress made in antimicrobial therapy.

Chapter 23, entitled Copper-Based Nanoparticles as Antimicrobials, prepared by Kleoniki Giannousi et al., focuses on the antibacterial activity of CuO, Cu2O nanoparticles (NPs), and copper composites—Cu/Cu2O—covered by polymers or embedded into matrices, since the composition of the NPs results in different mechanisms of action. The size- and shape-dependent effects are highlighted as well as the synthetic conditions that have been applied for the preparation of the NPs. Special attention is given to the antifungal activity of Cu-based NPs.

Chapter 24, prepared by Amedea B. Seabra, entitled Antimicrobial Applications of Superparamagnetic Iron Oxide Nanoparticles: Perspectives and Challenges, presents and discusses what makes SPIONs so unique, showing recent progress, drawbacks, and challenges in the design of SPIONs as nanocarriers for antimicrobial agents. It is intended to be a source of inspiration for new developments in this promising field.

Alexander Lykov et al. in Chapter 25, entitled Silica Nanoparticles as a Basis for Efficacy of Antimicrobial Drugs, give an up-to-date overview of the screening of the therapeutic efficacy of silica-loaded antibiotics, in comparison with their officinal forms, based on the dynamics of growth of Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli in vitro and in experimental models of sepsis induced by various strains of microorganisms in mice. The expediency of using this modification of antibiotics to enhance their therapeutic efficacy in experimental sepsis is demonstrated.

Chapter 26, entitled Silver Nanoparticles as Antimicrobial Agents: Past, Present, and Future, prepared by Luciano Paulino Silva, describes the current state of the art on the use of AgNPs and their derived products for control and prevention of microorganisms and beyond with an emphasis on potential therapeutic and industrial applications related to novel products and processes.

Gennaro A. Dichello et al. in Chapter 27, entitled Encapsulation of Lethal, Functional, and Therapeutic Medicinal Nanoparticles and Quantum Dots for the Improved Diagnosis and Treatment of Infection, focus on areas where nanoparticle approaches, such as the evolution of heat or light via conjugated metals, have significant potential to treat infections produced by resistant bacteria. These areas might include the targeted delivery of antibiotics, environmentally tunable delivery of antibiotics, and nanoparticle-based bacterial diagnostics for detection, quantification, and identification.

Chapter 28, prepared by Marija Vukomanović, entitled Advanced Nanocomposites With Noble Metal Antimicrobial Nanoparticles: How to Design a Balance Among Antimicrobial Activity, Bioactivity, and Safe Delivery to the Place of Infection, presents an up-to-date overview of the design of selective antimicrobial nanoparticles capable of making a difference between bacterial and human cells.

Chapter 29, prepared by Gabriel Henrique Hawthorne et al., entitled Clinical Development in Antimicrobial Nanomedicine: Toward Novel Solutions, reviews the clinical trial concept and the procedures of each step. Trials addressing nanoparticles on catheters, hand gels, therapeutic vaccines, safety, and other issues are presented in this chapter.

Chapter 30, entitled Recent Citation Classics in Antimicrobial Nanobiomaterials, prepared by Ozcan Konur, gives an overview of the scientometric research in antimicrobials and nanomaterials as well as antimicrobial nanobiomaterials. Major research areas are silver nanoparticles and other antimicrobial nanobiomaterials such as graphene and ZnO. Research into antimicrobial nanobiomaterials has robust public policy implications providing strong incentives for the key stakeholders involved in antimicrobials research.

Anton Ficai,     University Politehnica of Bucharest, Bucharest, Romania

Alexandru Mihai Grumezescu,     University Politehnica of Bucharest, Bucharest, Romania,     Academy of Romanian Scientists, Bucharest, Romania

Chapter 1

Antimicrobials

Meeting the Challenges of Antibiotic Resistance Through Nanotechnology

Bhaskar Das, and Sanjukta Patra     Indian Institute of Technology Guwahati, Guwahati, India

Abstract

Antibiotics are one of the antimicrobials that have been widely exploited to control infectious diseases. The successful use of antibiotics is challenged by the rapid emergence of antibiotic resistance and the need for better methods of delivery. To overcome the problem of drug resistance, novel antimicrobial agents are needed to which the clinical isolates cannot easily develop resistance. Nanomaterials seem to be an answer to the problem because their antimicrobial effects are dependent on their ability to affect multiple biological pathways. To develop microbial resistance to antimicrobial nanoparticles (NPs), concurrent mutations have to occur making development of microbial resistance to NPs less likely. The utilization of nanocarriers for conventional antibiotics has been proven to enhance their antimicrobial activity against drug-resistant microbial strains showing potential to overcome the growing menace of drug resistance. This chapter highlights the current advances underlying emergence of antibiotic-resistant pathogens and endorses the use of nanomaterials to counteract antimicrobial resistance and the delivery of antimicrobial drugs.

Keywords

Antibiotic resistance; Antimicrobials; Better delivery; Nanoparticle-based delivery

Chapter Outline

1. Introduction

2. Current Status of the Menace of Antimicrobial Resistance

3. Antimicrobial Classes and Their Current Effectiveness With Respect to Emerging Drug Resistance

3.1 Classification on the Basis of Spectrum of Activity

3.2 Classification on the Basis of Nature of Effect

3.3 Classification on the Basis of Mode of Action

3.3.1 Cell Wall Synthesis Inhibitors

3.3.2 Cell Membrane Function Inhibitors

3.3.3 Protein Synthesis Inhibitors

3.3.4 Nucleic Acid Synthesis Inhibitors

3.3.5 Metabolic Process Inhibitors

4. Microbial Resistance Mechanism to Antimicrobials

4.1 Antibiotic Inactivation

4.1.1 Hydrolysis-Based Antibiotic Inactivation

4.1.2 Group Transfer-Based Enzymatic Inactivation

4.1.3 Redox Process-Based Antibiotic Inactivation

5. Application of Nanotechnology to Counter Antimicrobial Resistance

5.1 Nanomaterials as Antimicrobials

5.1.1 Silver Nanoparticles

5.1.2 Zinc Oxide Nanoparticles

5.1.3 Titanium Dioxide Nanoparticles

5.1.4 Gold Nanoparticles

5.1.5 Copper Nanoparticles

5.1.6 Chitosan

5.1.7 Nitric Oxide-Releasing Nanoparticles

5.1.8 Carbon Nanotubes

6. Role of Nanoparticles in Overcoming the Challenge of Antimicrobial Drug Delivery

6.1 Liposome-Mediated Antimicrobial Delivery

6.1.1 Polymeric Nanoparticles

6.1.2 Solid Lipid Nanoparticles

6.1.3 Dendrimers

7. Conclusions

Acknowledgment

References

Further Reading

1. Introduction

Antimicrobials are probably one of the most successful forms of chemotherapy in medical history and have contributed significantly to controlling infectious diseases that threaten the existence of human civilization (Aminov, 2010). The word antimicrobial is derived from the Greek words anti (against), mikros (little), and bios (life) and refers to agents that kill microorganisms or cause growth inhibition. Antibiotics are substances that are produced by microorganisms that inhibit or kill other microorganisms. On the contrary, an antimicrobial is a natural (plant or animal), semisynthetic, or synthetic substance that kills or inhibits microbial growth with no or minimal damage to the host. Antimicrobials act against all microbial varieties and thus are classified according to the microbial group they act against. Antibacterials act against bacteria, antivirals act against viruses, antifungals act against fungi, and antiprotozoals act against protozoa (www.amrls.cvm.msu.edu). Antimicrobials that kill microbes are known as microbicidal, while those that inhibit microbial growth are referred to as biostatic. Use of antibiotics is not only restricted to the modern antibiotic era but dates back to ancient civilizations. Traces of tetracycline have been determined in human skeletal remains from the ancient Sudanese Nubia dating back to 350–550 CE, and Roman period skeletons from Egypt indicated exposure to tetracycline-containing material in their diet (Nelson et al., 2010; Basset et al., 1980). In India, Ayurveda, the oldest healthcare system in the world (about 5000  years old), has references to various types of microorganisms that cause diseases and stresses the need to destroy them to preserve human health. Many Ayurvedic drugs were known to be effective against common microbial infections such as Mycobacterium tuberculosis (treated by Suvarna Bhasma or gold calyx), malaria (treated using Mahasudarshan Kwath), and surgical prophylaxis (treated using Triphala Guggulu) (Sharma et al., 2014). With the advent of the germ theory of disease, the vital role of microbes in causing infectious diseases has been established, setting the stage for the beginning of the modern antibiotic era. The major breakthrough in field of antibiotics came in 1928 when Alexander Fleming discovered the antibiotic penicillin from Penicillium rubens. Penicillin has found clinical applications to successfully treat many fatal infectious diseases such as Streptococcus infection, gonorrhea, strep throat, and pneumonia. In 1935, Gerhard Domagk developed the first synthetic antibacterial sulfonamide with tremendous clinical success in treating diseases such as meningitis, child bed fever, and pneumonia. The discovery and clinical application of such antibiotics set the paradigm for the search for new antimicrobials by other researchers. The clinical value of an antimicrobial would be compromised by development of microbial resistance against it. Even before the clinical use of antibiotics, Alexander Fleming's research group discovered a bacterial penicillinase that can inactivate penicillin. Uncontrolled widespread use of penicillin resulted in the emergence of penicillin-resistant strains, mostly Staphylococci, and most countries restricted penicillin use by prescription only. To counteract this, a semisynthetic penicillin variety, methicillin, which is insensitive to penicillinase, was developed and used successfully for antibacterial chemotherapy. However, after few years of clinical use, methicillin-resistant strains of Staphylococcus aureus (MRSA) emerged, which has become a current challenge faced by antimicrobial therapy worldwide. The pattern of emergence of antibiotic resistance is the same for other antibiotics that were commercially available in the latter half of the 20th century (www.amrls.cvm.msu.edu). Mortality rates caused by multidrug-resistant bacterial infection have been reported to be quite high in the European Union and the Unites States, being 25,000 and 63,000 patients per year, respectively. Scientists have warned that the world will return to a preantibiotic era plagued by life-threatening microbial infections on the basis of a recent antibiotic resistance gene database that lists the existence of more than 20,000 antibiotic-resistant genes of 400 types predicted from available genome sequences (Liu and Pop, 2009). Thus discovery of novel antimicrobial agents to which microbes cannot develop resistance easily is one of the major medical concerns of the 21st century. The development of new antimicrobials alone will not be effective for antimicrobial therapy unless efficient drug delivery strategies are developed. Inefficient drug delivery would result in decreased therapeutic index of the antimicrobials along with local and systemic side effects. The current clinical application of nanotechnology has the potential to revolutionize antimicrobial therapy by overcoming the problems associated with conventional therapy. Nanoparticles (NPs) could serve as novel antimicrobial agents with less chances of development of microbial resistance (Huh and Kwon, 2011). Also the therapeutic index of antimicrobials can be improved by loading drugs on NP-based carriers, in contrast to its free drug counterparts. Use of NPs for antimicrobial delivery will significantly increase the drugs' serum solubility, prolong the lifetime of systemic circulation of the drug, sustain drug release in target tissues, and make use of combination therapy by delivering multiple drugs to the same target cell (Zhang et al., 2010). Because of the seriousness of these issues in antimicrobial therapy, we need to review the current scientific advancements related to understanding the mechanisms of microbial antibiotic resistance, the counter strategy against antibiotic-resistant pathogenic strains, and antimicrobial drug delivery. In this chapter, we will comprehensively review the current advances underlying the emergence of antibiotic-resistant pathogens, the strategies employed to counteract antimicrobial resistance, and the delivery of antimicrobials using nanostructured biomaterials.

2. Current Status of the Menace of Antimicrobial Resistance

Each time an antibiotic is used for treatment of microbial infections in humans or animals the probability of spread of antibiotic resistance looms large (Austin et al., 1999). Inappropriate antibiotic use has led to the evolution of pathogenic epidemic-causing organisms into multidrug-resistant forms (Davies and Davies, 2010). In spite of the high global risks associated with antimicrobial resistance it has been given low priority in both developing and developed nations. Each nation must adopt a strategy to fight antimicrobial resistance tailored to its conditions. The problem is graver in developing nations where easy availability, use of antibiotics in inappropriate high doses, and cost constraints to replace older antibiotics with new expensive antibiotics increase the probability of increased production of antimicrobial-resistant strains (Kumar et al., 2013). A widely known form of antibiotic resistance is New Delhi metallo-β-lactamase-1 (NDM-1) produced by the gene blaNDM-1, which is plasmid borne and could be transferred between the bacterial species Klebsiella pneumoniae and Escherichia coli. This has resulted in strains with broad antibiotic resistance including carbapenems. Multidrug-resistant M. tuberculosis, a 20th century version of an old pathogen, infects one-third of the world's population in both developed and developing countries. The effectiveness of antituberculosis drugs has been compromised by the rapid emergence and spread of strains resistant to four or more frontline tuberculosis treatments, i.e., extremely drug-resistant strains and totally drug-resistant strains (Davies and Davies, 2010). The causative organisms of hospital-acquired infections (HAIs) have become a matter of concern worldwide. MRSA has the reputation of being the most notorious multidrug-resistant superbug causing nosocomial infections. From being a causative organism in HAIs, MRSA has now become a major community-acquired pathogen combined with the characteristics of enhanced virulence caused by acquired pathogenic genes encoding cytotoxic Panton–Valentine leukocidin (Davies and Davies, 2010; DeLeo and Chambers, 2009). Pseudomonas aeruginosa originally caused burn wound infection and developed into a major nosocomial infection. Metallo-β-lactamase-producing P. aeruginosa has shown resistance to carbapenems. The rapid emergence of multidrug-resistant Enterobacteriaceae-producing extended spectrum β-lactamases (ESBLs), ESBL-producing K. pneumoniae, ciprofloxacin-resistant Salmonella enterica serovar Typhi, the emergence of vancomycin-intermediate Staphylococci, fluoroquinolone-resistant Salmonella, and P. aeruginosa and Acinetobacter baumannii resistant to ceftazidime, cefepime, and ciprofloxacin is a matter of concern to antimicrobial therapy (Kumar et al., 2013). Genome studies on A. baumanni showed the presence of at least 28 genomic islands encoding determinants for antibiotic resistance, explaining the serious concerns raised because of the rapid emergence of drug-resistant strains of A. baumanni (Davies and Davies, 2010; Gomez and Neyfakh, 2006). A hypervirulent and toxic HAI strain of Clostridium difficile has emerged because of the extensive use of antibiotics as expanded spectrum cephalosporin, newer penicillins, and fluoroquinolones (Davies and Davies, 2010). The influenza A (H1N1) virus responsible for the recent outbreak of avian influenza worldwide was found to be susceptible to neuraminidase inhibitors oseltamivir and zanamivir. However, resistance to oseltamivir was reported in June 2009 and since then 570 oseltamivir-resistant cases have been reported worldwide (Potdar et al., 2013). Because of the pressing nature of the problem of antibiotic resistance, it is high time to raise awareness about this problem and develop efficient strategies to tackle it.

3. Antimicrobial Classes and Their Current Effectiveness With Respect to Emerging Drug Resistance

Antimicrobials are classified based on a variety of methods such as spectrum of activity, effect on microbes, and mode of action.

3.1. Classification on the Basis of Spectrum of Activity

If an antibacterial is active against both Gram-positive and Gram-negative bacteria it is referred to as a broad spectrum antibacterial, e.g., tertracyclines, phenicols, third and fourth generation cephalosporins, and fluoroquinolones. On the other hand, an antibacterial that is effective against a particular species of microbe, e.g., glycopeptides and bacitracin are effective only against Gram-positive bacteria, polymyxins are effective only against Gram-negative bacteria, aminoglycosides and sulfonamides are effective only against aerobic organisms, and nitoimidazoles are effective against anaerobes (www.amrls.cvm.msu.edu).

3.2. Classification on the Basis of Nature of Effect

Based on the nature of effect on bacteria, antibiotics are classified as bactericidal (which kill the target bacteria) and bacteriostatic (which inhibit bacterial growth and replication), e.g., antibiotics such as aminoglycosides, cephalosporins, penicillins, and quinolones are bactericidal, while tetracyclines, sulfonamides, and macrolides exert bacteriostatic effects on target bacteria. The effect of bactericidal agents is faster as compared to bacteriostatic agents. Bacteriostatic agents require an effective immune system in the host for elimination of pathogenic bacteria and hence are not applicable to immunosuppressed host conditions or acute infections. However, some antibiotics may behave as both bacteriostatic and bactericidal based on dosage concentration and duration of exposure, e.g., aminoglycosides, fluoroquinolones, and metronidazole exert concentration-dependent bactericidal characteristics (www.amrls.cvm.msu.edu).

3.3. Classification on the Basis of Mode of Action

The mode of action of antimicrobials varies on the basis of the nature of their structure and degree of affinity to target sites within bacterial cells.

3.3.1. Cell Wall Synthesis Inhibitors

Since the cell wall is critical for the survival of bacterial species, an antibacterial that affects the cell wall would behave as a bacteriostatic or bacteriocidal agent. The β-lactam group of antibiotics contains a four-membered nitrogen-containing β-lactam ring responsible for its antibacterial action. β-Lactam antibiotics bind to penicillin-binding proteins (PBPs) present on the cell membrane rendering them incapable of performing cell wall synthesis (Elander, 2003). This kills the target bacteria by osmotic instability or autolysis, e.g., natural penicillin, penicillinase-resistant penicillin such as methicillin, nafcillin, and oxalin, extended spectrum penicillin such as ampicillin, carbenicillin, and amoxicillin, cephalosporins, carbapenems, and monobactams. Carbapenems and second, third, and fourth generation cephalosporins have broad spectrum activity, while penicillin, first generation cephalosporins, and monobactams have a narrow spectrum of activity. The activity of β-lactams varies among bacterial species on account of species-specific variation of PBP content and nature. Gram-negative bacteria with an outer membrane layer hinder the interaction of PBP and β-lactam antibiotics, thus rendering the antibacterial ineffective. The glycopeptide group of antibiotics inhibits bacterial cell wall synthesis by binding to precursors of cell wall synthesis, which leads to the inhibition of cell wall synthesis activity by PBPs. Actinomycetes species such as Streptomyces orientalis and Nocardia actinoides produce the glycopeptides vancomycin and actinoidin, respectively. These drugs have a narrow spectrum of bactericidal activity affecting only Gram-positive bacteria. Vancomycin is considered a last resort drug for the treatment of skin and bone infection, bloodstream infection, endocarditis, and meningitis caused by MRSA (www.amrls.cvm.msu.edu).

3.3.2. Cell Membrane Function Inhibitors

Exchange of intra- and extracellular substances takes place through microbial cell membranes. Thus cell survival can be at stake if there is disruption of cell membrane structure because of leakage of important intercellular solutes. Cell membrane is found in both prokaryotic and eukaryotic organisms causing poor selectivity and thus compromising its use in the mammalian host, e.g., polymyxin (www.amrls.cvm.msu.edu). The polymyxin group of antibiotics is characterized by a cyclic peptide with a long hydrophobic tail. Polymyxins bind to lipopolysaccharides (LPS) in the outer membrane of Gram-negative bacteria and disrupt the cell membrane structure. The hydrophobic tail with its detergent-like mode of action is instrumental in damaging the cell membrane. Their specificity to LPS molecules that exist in the outer membrane of Gram-negative bacteria renders them selective to bactericidal activity against Gram-negative bacteria. They are produced by nonribosomal peptide synthetase systems in Paenibacillus polymyxa (www.nlm.nih.gov). On account of their neurotoxicity and nephrotoxicity, polymyxins are used as a last resort when other clinical antibiotics prove ineffective (Falagas and Kasiakau, 2006). They have found application in controlling infection caused by multiple drug-resistant P. aeruginosa and carbepenemase-producing Enterobactericeae. Colistin is a polymyxin antibiotic that confers its bactericidal activity to its polycationic nature with both hydrophilic and lipophilic moieties. The polycationic regions interact and displace bacterial counter ions from LPS present in the bacterial outer membrane. Hydrophobic and hydrophilic regions interact with the cytoplasmic membrane solubilizing the bacterial membrane leading to bactericidal activity. Colistin is produced by P. polymyxa var. colistinus. In India, colistin is commercially available as Colymonas and Koolistin. Although it is not favored because of nephrotoxic effects, it is considered a last resort antibiotic against multidrug-resistant P. aeruginosa, K. pneumoniae, and Acinetobacter, etc. (Falagas et al., 2008). Colistin susceptibility is also observed in NDM-1 metallo-β-lactamase multidrug resistant Enterobacteriaceae (Kumarasamy et al., 1999).

3.3.3. Protein Synthesis Inhibitors

One of the vital processes for microbial multiplication and survival is protein synthesis. With an attempt to kill or inhibit the growth of pathogenic microbes, many antimicrobials disrupt the protein synthesis machinery by binding to the 30S or 50S subunit of intracellular ribosomes, e.g., aminoglycosides, macrolides, lincosamides, streptogramins, chloramphenicol, and tetracyclines (www.amrls.cvm.msu.edu).

3.3.3.1. Aminoglycosides

Inhibition of protein synthesis by aminoglycosides is caused by its binding to the 30S ribosomal subunit. This perturbs peptide elongation at the 30S ribosomal subunit resulting in errors during mRNA translation and thus biosynthesis of truncated proteins that bear altered amino acid compositions (Mingeot-Leclercq et al., 1999). Aminoglycosides are derived from bacteria of the genus Streptomyces and Micromonospora (Kroppenstedt et al., 2005). They are useful to treat infections caused by aerobic, Gram-negative bacteria such as Pseudomonas, Acinetobacter, Enterobacter, and tuberculosis-causing mycobacteria. Although its clinical use is limited because of nephrotoxicity and ototoxicity, the recent emergence of antibiotic-resistant Gram-negative bacterial strains has led to interest in reevaluating its antimicrobial susceptibility and toxicity. The encouraging fact is that aminoglycosides still retain activity against the majority of clinical bacteria in many parts of the world providing means to overcome antibiotic resistance (Durante-Mangoni et al., 2009; Falagas et al., 2008), e.g., streptomycin was the first effective clinical drug to treat tuberculosis.

3.3.3.2. Macrolides

The macrolides group of antibiotics is characterized by the presence of a macrolide ring belonging to the polyketide class of natural products. Macrolides inhibit protein biosynthesis by binding to the P site on the 50S ribosomal subunit leading to prevention of peptidyl transferase by adding a growing peptide attached to tRNA to the next amino acid as well as inhibition of ribosomal translation (www.pharmacologycorner.com). Premature dissociation of peptidyl-tRNA from ribosome is another potential mechanism (Tenson et al., 2003). Macrolides are transported to the site of infection because they are concentrated within leukocytes (Bailly et al., 1991). Natural macrolides are produced by Saccharopolyspora erythraea (erythromycin) and Streptomyces fradiae (tylosin), while some are semisynthetic such as tilmicosin and tulathromycin (www.amrls.cvm.msu.edu). Macrolides were used to treat clinical infections caused by Gram-positive organisms with a slightly wider spectrum of activity compared to penicillin (www.emedexpert.com). They are used as a substitute for penicillin allergic patients. Macrolides are effective against β-hemolytic streptococci, pneumococci, staphylococci, enterococci, and pathogens against which penicillin activity fails. However, macrolide-resistant bacterial strains have been developed by posttranscriptional methylation of 23S bacterial ribosomal RNA, which is a matter of concern.

3.3.3.3. Lincosamide

The lincosamide group of antibiotics shows effectiveness against bacteria by applying an inhibitory effect on protein synthesis via binding to the 23S portion of the 50S bacterial ribosomal subunit. Protein synthesis is inhibited because of premature dissociation of peptidyl-tRNA from the ribosome (Tenson et al., 2003). As human ribosomes are structurally different from their bacterial counterparts, lincosamides do not interfere with protein synthesis in humans. Lincosides are effective in the control of Gram-positive bacteria, most anaerobic bacteria, and some Mycoplasma (www.amrls.cvm.msu.edu). Lincomycin, the first lincosamide, was isolated from Streptomyces lincolnensis. They also treat clinical infections related to Staphylococcus, Streptococcus, Bacteroides fragilis, and toxic shock syndrome. Lincosamide antibiotics are most associated with the treatment of pseudomembranous colitis caused by C. difficile (www.nlm.nih.gov/medline). Lincosamides may behave as bacteriostatic or bacteriocidal depending on drug concentration, bacterial species, and pathogen concentration. The matter of concern is that microbial resistance to lincosamide is conferred by 23S binding site methylation. This makes lincosamide-resistant strains also resistant to macrolides.

3.3.3.4. Streptogramins

The streptogramin class of antibiotics confers antibacterial activity by binding to the 50S ribosomal subunit leading to inhibition of protein synthesis. Group A steptogramins prevent peptide bond formation during the chain elongation step. Group B steptogramins release incomplete peptide chain from the 50S ribosomal subunit (www.amrls.cvm.msu.edu). An encouraging fact is that they are currently effective for treatment of two of the most rapidly growing multidrug-resistant bacterial strains, namely, vancomycin-resistant S. aureus and vancomycin-resistant Enterococcus (VRE).

3.3.3.5. Chloramphenicol

Chloramphenicol is bacteriostatic because of its capability to inhibit protein synthesis. Chloramphenicol hinders protein chain elongation by peptidyl transferase inhibition of bacterial ribosome (www.amrls.cvm.msu.edu). The natural source of its isolation is Streptomyces venezualae. Chloramphenicol was first used for the treatment of typhoid but with the global presence of multiple drug-resistant Salmonella Typhi it loses its clinical value. It is widely used for the treatment of bacterial conjunctivitis, staphylococcal brain abscesses (because of excellent blood–brain barrier penetration), and meningitis. It is used to treat infections caused by tetracycline-resistant cholera and VRE. Microbial chloramphenicol-resistant strains are conferred by the cat gene, which codes for an enzyme chloramphenicol acetyltransferase, which inactivates chloramphenicol. Reduced membrane permeability and 50S ribosomal subunit mutation are other microbial mechanisms that resist the effect of chloramphenicol. Chloramphenicol resistance may be carried in plasmids such as ACCoT plasmid, which confers multiple drug resistance against ampicillin, chloramphenicol, cotrimaxole, and tetracycline in typhoid (www.wikipedia.org/Chloramphenicol).

3.3.3.6. Tetracycline

Tetracycline inhibits cell growth by binding to the 16S part of the 30S ribosomal subunit preventing aminoacyl tRNA from binding to the ribosome A site. This leads to inhibition of translation hampering cell growth (Connell et al., 2003). Tetracyclines are used in the treatment of clinical conditions such as urinary tract infections, respiratory tract infections, acne, rosaceae, anthrax, bubonic plague, malaria, elephantiasis, syphilis, Lyme disease, etc. Nowadays, clinical application of tetracycline is being compromised by tetracycline resistance in the pathogenic microbes. In tetracycline-resistant microbial strains, tetracycline resistance genes encode a membrane protein that effluxes tetracycline out of the cell. Tetracycline resistance is also provided by blocking tetracycline from binding to ribosome or by enzymatic inactivation of tetracycline, which is rare (Wyk, 2015; www.wikipedia.org/Tetracyclines).

3.3.4. Nucleic Acid Synthesis Inhibitors

DNA and RNA are essential for microbial replication and survival. The antibacterial activity of some antibiotics lies in interfering with the nucleic acid synthesis processes, e.g., quinolones and rifamycin.

3.3.4.1. Quinolones

Quinolones are synthetic broad spectrum antibacterials that prevent bacterial DNA synthesis (Andersson and MacGowan, 2003). Fluoroquinolone is the most common quinolone used in antibacterial treatment. Fluoroquinolones bind to the DNA gyrase–DNA complex causing defects in the supercoiling of bacterial DNA. This causes enabling of replication and survival (www.amrls.cvm.msu.edu). Fluoroquinolones are broad spectrum antibiotics that are used for control of HAIs resistant to conventional antibiotic classes. However, the broad spectrum range of fluoroquinolones could lead to the spread of multidrug-resistant strains. Fluoroquinolones are used predominantly for the treatment of hospital- and community-acquired pneumonia caused by drug-resistant Streptococcus pneumoniae (MacDougall et al., 2005). They are also used for the treatment of hospital-acquired urinary catheter infection and polynephritis. In community-acquired infections, fluoroquinolones are recommended when antibiotic therapy fails on account of multidrug resistance (Liu and Mulholland, 2005).

3.3.4.2. Rifamycin

Rifamycin is a group of antibiotics whose activity depends on its high affinity for prokaryotic RNA polymerase inhibiting bacterial DNA-dependent RNA synthesis (Calvori et al., 1965). Rifamycins can enter neutrophils and macrophages and then inhibit bacterial DNA-dependent RNA polymerase (www.amrls.cvm.msu.edu). Their poor affinity to analogous mammalian enzyme renders them selective. They are synthesized either naturally by Amycolatopsis rifamycinica or artificially. Rifamycins are particularly effective against mycobacteria and therefore are used to treat tuberculosis, leprosy, and Mycobacterium avium complex infections. Multiple drug resistance is currently posing a threat to rifamycin-based treatment of tuberculosis (Floss and Yu, 2005).

3.3.5. Metabolic Process Inhibitors

Other antibiotics act as inhibitors of metabolic pathways essential for survival of bacterial pathogens, e.g., sulfonamides and trimethoprim (TMP).

3.3.5.1. Sulfonamides

The antibacterial activity of sulfonamides is caused by their interference with folic acid synthesis by preventing the addition of para-aminobenzoic acid into folic acid molecules by competitive inhibition of enzyme dihydropteroate synthetase (DHPS). Thus sulfonamides are bacteriostatic and not bactericidal. The first sulfonamide, trade name Pontosil, could treat infections caused by streptococci, blood infections, child bed fever, and erysipelas. The genetic basis of sulfonamide resistance lies in sul1, sul2, and sul3 genes encoding DHPS with low affinity for sulfonamide. A wide range of bacterial species harbor these genes in mobilizable plasmids manifesting multiple antibiotic resistance (Wang et al., 2014).

3.3.5.2. Trimethoprim

TMP is a synthetic antibiotic that binds with the enzyme dihydrofolate reductase (DHFR) inhibiting the folic acid synthesis pathway (Brogden et al., 1982). It is widely used in the treatment of urinary tract infections and Pneumocystis jiroveci pneumonia. However, because of the widespread use of TMP, TMP-resistant pathogenic strains have surfaced as a major clinical problem. The mechanism of TMP resistance includes cell wall impermeability to TMP, alternate metabolic pathways, and production of chromosomal or plasmid-mediated TMP-resistant DHFR enzyme (Huovinen, 1987).

4. Microbial Resistance Mechanism to Antimicrobials

In the late 1960s when the success of antimicrobial therapies for controlling infectious diseases was at large, US Surgeon General William H. Stewart made an infamous declaration that it is time to close the book on infectious diseases and declare the war against pestilence won. This common sentiment of the medical community at that time has since been proved inaccurate. The development of resistance to common antibiotics in the medical arsenal has brought us to a situation that microbial infections are the second leading cause of death worldwide (Spelberg et al., 2008). Thus understanding the biochemical resistance mechanism has become a significant biochemical issue.