Degradation of Antibiotics and Antibiotic-Resistant Bacteria From Various Sources

By Pardeep Singh and Mika Sillanpaa

The excessive use of antibiotics has given rise to an increase in microbial resistance, threatening our ability to treat infectious diseases. The growth in resistance to antimicrobials and antibiotics threatens to reverse almost a century of medical progress. urgent action plans to tackle the crisis of Antimicrobial Resistance (AMR) and multi-resistant bacteria are needed.

It is a major research task to find effective ways to reduce the release and degradation of antibiotics and ARBs to the environment. Degradations of Antibiotics and Antibiotic Resistance Bacteria from various sources addresses various issues related the generations and degradations, eliminations of antibiotics and antibiotics resistance bacteria.

Degradations of Antibiotics and Antibiotic Resistance Bacteria from various sources contains both practical and theoretical latest and broad aspects of antibiotics and antibiotics resistance bacteria management through the various recent methods. Various factors which are responsible for the efficient degradations are highlighted in the Degradations of Antibiotics and Antibiotic Resistance Bacteria from various sources as separate chapters. Socioeconomic and policies on the ARBs are also discussed.

• Contains both practical and theoretical latest and broad aspects of antibiotics resistant bacteria
• Emphasizes the health impact of antibiotic resistance and genes
• Gives insight in the applications of anaerobic digestions for eliminations of ARBs (antibiotic resistance blockers) and ARGs (Antibiotic Resistance Genes)
• Shows how ARB’s influences the degradation processes and management

• Language: English
• Publisher: Academic Press
• Release date: Sep 30, 2022
• ISBN: 9780323914628

Book preview

Chapter 1

Antibiotic resistance: retrospect and prospect

Bilal Aslam¹, Moeed Ahmad¹, Muhammad Usama Tariq¹, Saima Muzammil¹, Abu Baker Siddique¹, Mohsin Khurshid¹, Aqsa Shahid¹, Muhammad Hidayat Rasool¹, Tamoor Hamid Chaudhry², Afreenish Amir², Muhammad Salman² and Zulqarnain Baloch³,    ¹Department of Microbiology, Government College University Faisalabad, Faisalabad, Pakistan,    ²Public Health Laboratories Division, National Institute of Health, Islamabad, Pakistan,    ³Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, P.R. China

Abstract

After discovery, antibiotics changed modern medicine substantially and augmented human life expectancy by 20 years. The emergence of multidrug-resistant pathogens and the dearth of new antibiotics led to the current soaring crisis of antibiotic resistance. According to the recent O’Neill report published by The UK around 10 million people may die from infections caused by multidrug-resistant superbugs by 2050. In this regard drug discovery is one of the most related recommendations. In this chapter, an overview of antibiotics and the evolution of antibiotic resistance will be given along with some future aspects. For instance there may be a bright future to come for drug discovery, as a lot of high throughput technologies like genome editing and mining are being deployed to find the new antibacterial natural products with different bioactivities or engineered/chimeric therapeutic proteins, that is, phage endolysins, lysibodies, and enzybiotics.

Keywords

Antibiotics; antibiotic resistance; future of antibiotic resistance; antibiotic discovery

1.1 Introduction to antibiotics

The term antibiotic is defined by S.A. Waksman as the substance chemically produced by the bacteria that either inhibit or destroy bacteria and many other microbes (Waksman, 1947). Within the biosynthetic antibiotic operon, the naturally producing antibacterial species have resistant genes to that antibacterial to avoid the self-toxicity (Davies, 1994). Now, the antibiotic term is more broadly used and includes any of the antimicrobial compounds either of the synthetic or natural origin (Mohr, 2016). The antibiotics kill by disrupting the microbial structures, selective toxicity, or by the processes that normally do not occur in the human cell and their development depends on the theory of the antibiosis that reflects the first proven antibiosis phenomenon by experiments, that is, The antagonist effects of penicillin on the bacteria (Landecker, 2016). From the beginning of an antibiotic era in the 1950 amount of the antibiotics produced is surely very significant one may be astonished that the antibiotics were also produced in the barely in the soil in remarkable amount (Davies, 2006). The mass production of penicillin in 1944 pre-World War 2 era was aided by some pharmaceutical giants such as Merck, Pfizer and Squibb and also by the United States Department of Agriculture (Bud, 2007). The productions were released to the public in 1945 by the US, it was approximated as 270 lb which was for 9 million people per month (Landecker, 2016). In 1945 E.B Chain, A. Fleming, and H.W Florey were awarded the noble prize for their discovery of renowned penicillin and its curing effect against various infective diseases (Savignano). From ancient times almost 1000 years ago evidence has shown that people used antimicrobial remedies, that is, antibiotics for treating various infections and that recipe is still very effective against Methicillin-resistant Staphylococcus aureus (MRSA) (Harrison et al., 2015). The John Parkinson book, that is, Theatrum Botanicum was published in 1640, has evidence that the ancient Egyptians, Greeks, and some other civilizations of that time used moldy bread for treating infections (Gould, 2016). Evidence had made it clear that from the ancient civilization many people used naturally occurring antimicrobial products like honey, herbs, and even in many cases animal feces (Keyes et al., 2008).

1.1.1 Natural products as conventional antibiotics and their derivatives

The US Food and Drug Administration (US FDA) has reported several new drugs every year (US FDA). Most of them are of natural origin,that is, natural products or they may be the derivatives of some other naturally occurring products, that is, semisynthetic products (Kinch et al., 2014; Katz and Baltz, 2016). The microorganisms in the natural environment, by the production of antimicrobial substances, have to fight against each other and thus develop a mechanism of resistance to other antimicrobials (Raoult, 2016). The purification of antibiotics for decades from microbial origin has investigated an estimated 28,000 compounds and 200 of them have been directly used as drugs (Van Boeckel et al., 2014). Some nanoparticles and their semisynthetic derivates have been used for decades for the treatment of many Gram +ve and Gram –ve of bacterial infections in animals and humans. The clarithromycin or azithromycin and both of the semisynthetic macrolide erythromycin derivatives, doxycycline, amoxicillin, second generation of tetracycline and cephalexin, semisynthetic penicillin, cephalosporin derivatives are all most commonly used for the treatment of respiratory or bacterial skin infection (Katz and Baltz, 2016). A major foundation has been provided by the natural products for developing antibiotic drugs. To provide the new molecular structure the reliance on the natural product is established well for almost every disease (Patridge et al., 2016). Only three of the antibiotic classes out of nine of which six are naturally originated compounds, the fluoroquinolones, oxazolidinones, and sulfonamides are conceived completely through synthetic chemistry. Within the antibiotics of natural products, an impressive diversity of structure and complexity has been noted especially when they are compared with the synthetic classes. (Rossiter et al., 2017). Many great opportunities have been offered by natural products. Streptomyces clavuligerus was noted as a beta-lactam antibiotic producer from which the first inhibitor of the beta-lactamase, that is, clavulanic acid was isolated. In addition to the source of the antibiotic, microbes are also the source of inhibitors of resistance. An inhibitor of the metallo-beta-lactamase, that is, Aspergillomarasmine A was isolated from a species of fungus (King et al., 2014). For the majority of the current present antibiotics, Actinomycetales is the major source. Waksman Platform has frequently re-investigated the known compounds that can be easily identified from the extract of these bacterial species (Cox et al., 2017a). There is an opportunity for the plant’s naturally originated products as the antibiotic adjuvant and some molecules like berberine already have been shown as inhibitors of the efflux (Lewis and Ausubel, 2006). In the mid of 20th century, the first useful clinically significant macrolide antibiotics were isolated during the golden era of antibiotics from species of actinomycete Saccharopolyspora erythrea (Mc et al., 1952). Vancomycin (4) was the proto-typical glycopeptide that was isolated in 1955 by McGuire and co-workers from Actinobacter at Eli Lilly as a potent antibiotic (Mccormick et al., 1955).

1.2 Antibiotics timeline

A long time ago before the advancement in medicine antibiotic was used. Since ancient Egypt for treating wounds and burns, the effects of the bread on which filamentous fungi grows was commonly known (Pećanac et al., 2013). Musty textures were used in Greece and China in the middle ages for treating various ailments. Sir John Scott Burden Sanderson had noticed in the 19th century that the bacteria were absent from the liquid growth culture media that was covered with the mold. Joseph Lister in 1871 by using Penicillium glaucum extract discovered the effects of its inhibition on bacterial growth while treating an injury of a nurse. Louis Pasteur at the same time found that most of the bacteria inhibit some other bacteria. In 1877 Jules François with his colleague Joubert discovered that growth for Bacillus anthracis was inhibited by studying the urine samples when it was co-cultivated with the common aerobics bacteria. Jean Paul Vuillemin in 1889 purposed antibiosis as any relationship of biology in which one organism kills the other to ensure for its existence. in 1897 in the thesis work of Ernest Duchesne, many antagonisms between the microorganisms were published most notably for the molds. Around 30 years before Fleming discovered the P. glaucum inhibition for Escherichia coli. None of the antimicrobial molecules was purified despite several observations of antagonisms between the microorganisms. Chemical compounds were the first antimicrobial molecules that were discovered (Pećanac et al., 2013; Durand et al., 2019). In 1928 by Sir Alexander Fleming, the modern era for antibiotics was initiated by the discovery of penicillin (Sengupta et al., 2013) (Fig. 1.1). Paul Ehrlich in 1910 led the development of the first antibiotic Salvarsan which was an arsenic-based antimicrobial agent and was used for treating causative agents for Syphilis (Gelpi et al., 2015). Prontosil was discovered by Gerhard Domagk which was a sulfonamide Based drug. A remarkable development for other sulfonamides due to the rapid success of Prontosil as the chemotherapeutic agent had marked the age of chemotherapy from the sulfonamide era that was developed for infectious diseases (Otten, 1986). The discovery of sulfonimides by Domagk had very increased the activity against the infectious disease with penicillin (Suarez and Gudiol, 2009). lysozyme is an antibacterial enzyme discovered by Fleming (Fleming, 1945). In the 1930s and 1940s René Dubos by the discovery of an enzyme that was isolated from soil Bacillus had managed to decompose the S. pneumoniae type III capsular polysaccharide (Avery and Dubos, 1930) and also an Oligopeptide, that is, gramicidin from the Bacillus brevis (Dubos and Hotchkiss, 1941). About 55% of all the antibiotics discovered between 1945 and 1978 originate from the genus Streptomyces (Embley and Stackebrandt, 1994). Selman Waksman introduced culture techniques and many strategies (Waksman platform) for highlighting the antagonisms between some bacterial species and had performed systematic research on antimicrobial activities of the soil bacteria, mainly from the Streptomyces member or the streptomycetes. He developed several culture techniques and strategies (Lewis, 2012). During the 1940s a lot of important antifungals and antibiotics, such that of actinomycins especially from Streptomyces species, used the Waksman platforms (Waksman et al., 1946). The others antibiotic includes neomycin (from the Streptomyces fradiae), streptomycin (from the Streptomyces griseus), clavacin (from the Aspergillus clavatus) and fumigacin (from the Aspergillus fumigatus). Streptomycin, actinomycin, and neomycin have been still in the use nowadays (Durand et al., 2019). Multidrug resistant (MDR) tuberculosis treatments had developed by the finding of streptomycins (Kerantzas and Jacobs, 2017). Conversely, all the classes of these antibiotics were revealed within the first of the four decades of antibiotics innovation. Later 50 years of discovery, none of the new classes has been established (Fig. 1.1). The industries had turned to the in vitro creation of the new molecule. Consequently, two molecules known to be from the middle of the 20th century has known since 1955 and 1986 have been commercialized into the linezolid in 2003 and daptomycin in 2001 correspondingly (Lewis, 2013). Meanwhile, at the turn of the 1990s, commercialization and development of the novel antibiotic have been slowed. Between 2017 and 2019, different 11 new antimicrobials therapy had permitted by the US FDA (Sorscher, 2010). Of these 11 antimicrobials, four had accepted by the Europeans Union, Europeans Medicines Agencies (EU EMA), that is, meropenem vaborbactam combinations (Vaborem’s), eravacyclines (Xerava), delafloxacins (Quofenix/Baxdela), and the imipenem/cilastatin/relebactam combinations (Recarbrio). Toward granting of marketings authorizations positive view had recommended in December 2019, which the acceptance had been provided in February 2020 (De Oliveira et al., 2020). Distant from the these antimicrobial, through this times frames, EU EMA in addition approved to ceftobiproles (Zeftera), that is, also had approved by Australians Therapeutics Good Agencies in 2016 by the Canada health with in 2015, while Japanese Pharmaceuticals and Medicals Device Agencies (PMDA) had accepted the lascufloxacins (Lasvics) (Giacobbe et al., 2019; Canada, 2009). Worldwide initiatives to transport a new stand-alone antibacterials therapy or complementing alternatives therapy are instantly needed.

Figure 1.1 The timeline showing the development of various antibiotics along with their resistance.

1.3 The emergence of resistance

Each year 23,000 deaths are reported by the US (CDC) related to antibiotics in the USA, and in the upcoming decades, millions of death had been predicted by some (Durand et al., 2019). For the treatment of MDR and XDR bacteria, one of the strategies used in the past decades was to break the β-lactams vicious circle. Minocycline, fosfomycin, and colistin are active against the Gram –ve bacteria similar to sulfadiazine, clofazimine, and minocycline are active against XDR Mycobacterium strains (Kaye et al., 2017; Brouqui et al., 2017). In 1941 penicillin was given firstly to a patient. And so it goes on. In 1960 methicillin was introduced (Asif et al., 2018). Antibiotic resistance seemed like a part of then human modern conditions since 1958 (Landecker, 2016). Many new antibiotics between the late 1960s till the early 1980s were introduced by the pharmaceutical industries for the solution of the resistance problem (Spellberg and Gilbert, 2014). Mechanisms of actions of various commercially available antibiotics are described in Fig. 1.2. In 1972 against the methicillin resistant Staphylococcus aureus vancomycin was considered as a superbug (Sengupta et al., 2013). Vancomycin resistance for staphylococci (coagulase-negative) was reported in 1979 and after ten years resistance in enterococci was described (Courvalin, 2006). The less susceptible VISA, that is, vancomycin-intermediate S. aureus strain was reported in 1997 in Japan (Levine, 2006). In 1996 levofloxacin was introduced in the clinical practices and levofloxacin-resistant pneumococcus was also reported in the same year (Sengupta et al., 2013). Between 1960 and 1980, for almost two decades, new antimicrobials production was seen in adequate amounts by many pharmaceutical industries. After the 1980s discoveries for the new antibiotics classes had decreased dramatically until now when the new interest has been sparked (Parmar et al., 2018).

Figure 1.2 Target sites and mechanisms of action of various antibiotics from different classes.

1.4 Historical evidence of antibiotic-resistant genes

The occurrence of the antibacterial-resistant gene was demonstrated in the environment by D’costa and colleagues in which there were none of the innate antibiotics. They introduced existence as a reservoir for resistant determinant that mobilized in microbe community (D’costa et al., 2006). Gerard D. to purpose a collection of all antimicrobial resistance genes and their precursors gave the term resistome (Wright, 2007). Resistant genes against the antibiotics had also been found in the environment archeological samples. Million years before the blaOXA genes encoded β-lactamases had been reported (Barlow and Hall, 2002). Recently, 177 Genes of almost 23 families were resistant (represented mechanisms of the resistance, that is, efflux, mutation, and the inactivation of the antibiotic) were founded in the Mackay Glacier region (Van Goethem et al., 2018). Resistant genes for beta-lactams and the glycopeptide were also investigated and observed in 5300 years olden microbiome gut of the mummy Ötzi (Weber et al., 2017). Resistance genes for β-lactams glycopeptides and tetracyclines from the 30,000-year-old samples as permafrost were discovered by D’costa and King (2011). From 4 million years old 93 strains were cultured from the Lechuguilla Cave by the Bhullar and colleagues (New Mexico) and 65% of species showed resistance in vitro against three or the four antibiotic classes (Bhullar et al., 2012). From the soil to the human pathogenic species transfer of resistant genes from the environment producer is possible as it appears in some experimental studies (Jiang et al., 2017). A direct relationship between the emergence and dissemination of resistant strains of bacteria and the consumption of antibiotics had demonstrated in many epidemiological studies (Lushniak, 2014). Genes are inherited in bacteria from the relatives or may be acquired also from the none relatives on some mobile genetics elements like plasmids. These horizontal transfers may allow an antibiotic-resistant determinant to be transferred between different other species of bacteria. Resistant may also develop through spontaneous mutation. The antibiotics had removed the drugs sensitive contender that leave the resistant bacteria beyond that reproduced because of the natural selection. Despite warnings related to overuse, antibiotics were over-imposed throughout the world (Read and Woods, 2014; Gross, 2013). In many countries without prescription antibiotics are available and unregulated over the counter (Michael et al., 2014). Incorrectly prescribed antibiotics had contributed a lot to the promotion of resistant bacteria (Ventola, 2015; Van Boeckel et al., 2014). Many studies had shown that treatment indication, the choice of an agent, or the time for antibiotic therapy was wrong in almost 30%–50% of the cases (Luyt et al., 2014).

1.5 Global emerging threats

Conferring to the data of World Health Organization (WHO), infections triggered by MDRs bacterias caused deaths of about 700,000 of all ages, of which about 200,000 are newborns (Romandini et al., 2021). The biofilms linked to chronic situations is one of the major infections predisposing issue. The biofilm has associated with chronic consequent infection and also with the inherent resistance to antibiotics therapy. These infections caused by the biofilms can remain for months or even years, but good is that rarely fatal, but the often session becomes undisturbed by the antibiotics treatment. Treatments of infection triggered by the colonization of the biofilm often lead to fails, as this infection requires many antibiotics doses for extended times. Different explanations are there for such high resistants characters that can include, that is, (i) partial diffusion of these antibiotics inside these biofilms and altered the chemical microenvironments within these biofilms (Lewis, 2013) (Zhang and Bishop, 1996), (ii) persister cells are the those of subpopulations of bacterias in the extremely sheltered phenotypic states having a low or the arrested growths and they have started keeping on growing even after the removal of antibiotics stress. These are the contrivances that are considered to be associated with increased risks of the AMR (Cochran et al., 2000). The wide increasing number of human decides accounted actually for the MDR, that is, estimated to be increased to 10 million by 2050, surpassing the number of demises rising from cancer (Organization, 2014). Horizontal gene transfer (HGT) allows bacterias to interchange their genetic material, which includes the ARGs in the varied species of microbes (Le Roux and Blokesch, 2018). Recent studies disclose the rise of the superbugs, that have a wide count of HGT transfer ARGs on their plasmid can bear almost all of the antibiotics (Malhotra-Kumar et al., 2016). These types of plasmids found in MDRs are capable of more transfers to other various bacterial species, so creating new superbugs which can grow in many different environments. The global advent of superbugs resonant MDR plasmids, for example, MCR-1 and NDM-1 in the numerous environmental slots, for example, animals, patients, and soil that indicate the quick proliferation of MDR amongst a bacterial population. Though the HGT and MDRs originate to be strongly linked to superbugs, as discovered by following studies and to our awareness of how and to what extent HGTs propel the progress of MDRs under the diverse environmental’s condition remains inadequate (Sun et al., 2019).

1.6 Antimicrobial resistance in ESKAPE pathogens

Antimicrobial resistance of ESKAPE bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) poses a worldwide danger to the health of humans. The AGR acquired by the ESKAPE pathogens has limited treatment choices for severe infections, also increased disease load, and an increased mortality rate owing to the failure of treatment, necessitating a synchronized worldwide antimicrobial resistance surveillance response (De Oliveira et al., 2020). The WHO in 2017 issued a list of pathogens for those new antibiotics are required urgently to concentrate and steer research and development. ESKAPE pathogens (Rice, 2008) were given priority status within this broad category (Shrivastava et al., 2018). Resistance mechanisms have been developed by ESKAPE pathogens to antibiotics such as clinically unfavorable polymyxins, glycopeptides, and carbapenems as well as oxazolidinones, macrolides, lipopeptides, tetracyclines, fluoroquinolones, beta-lactam–lactamase and beta-lactams inhibitor combinations, and beta-lactam–lactamases inhibitor combinations (Zaman et al., 2017; Paterson and Bonomo, 2005). While the lipoglycopeptide resistance is uncommon and has been reported in recent past (Kussmann et al., 2018).

1.6.1 Resistant Staphylococcus aureus

In the 1960s many strains of MRSA was first reported as a threat in adult patient. Until the 1990s MRSA infection was rare among the children when this strain was firstly reported in adult infection and children had no earlier predisposing risk factor (Romandini et al., 2021). Thus from that time, the healthcare-acquired MRSA (HA-MRSA) began to circulate with the community-acquired MRSA (CA-MRSA). Sulfamethoxazole-trimethoprim and clindamycin had frequently used for the treatment of the CA-MRSA; resistance to sulfamethoxazole/trimethoprim was relatively uncommon, while the resistance for clindamycin had increased in past few decades (Sutter et al., 2016; Rasool et al., 2016). To limit the spread of MRSA the use of the mupirocin ointment had been put in practice in the past combined with the chlorhexidine baths and since those practices had started the resistance to chlorhexidine and mupirocin had emerged (Mcneil et al., 2011). Considering, the last resort for the treatment of MRSA infections, although in the 1997 first strain of the VISA or intermediate vancomycin susceptible S. aureus had isolated from the surgical wounds of the Japanese child, whose infections had not responded well to the vancomycin therapy for a long term (Hiramatsu, 1998). Ever since, vancomycin resistance had cast dark shades upon the anti-MRSA antibiotics treatments, especially for the children, whose therapeutics option remains to be fewer, including daptomycin and linezolid. Nevertheless, daptomycin is usually of no use in treatings lung infection as this bind to surfactants by its consequent inactivations (Kaushik and Kest, 2018). Fascinatingly, ceftaroline has a great efficiency on MRSA, upholding the cephalosporins along with varieties of signs both off or on the label (Pani et al., 2019). The MRSA strain that isolated the pediatric population in the US was the first epidemic wave studied and remained a frequent source of community illness in the Pacific Northwest and Alaska indigenous communities (David et al., 2008). In China between 2007 and 2018 the spread of CA-MRSA and HA-infection was historical. The H.A-MRSA clones for ST 239-037 and ST 239-030 prevalence decreased remarkably by 20.3% to 1% and from 18.4% to 0.5% and now ST 5-2460 clone replaced them from 0.0% to 17.30%, respectively and showed a quick emergence. The CA-MRSA clones ST 398 and ST 59 have also expanded in the same duration from 1.00% to 5.80% and from 1.8% to 10.5% (Dai et al., 2019). In Northern Europe a continuous decrease in the spread of the HA-MRSA was seen between 2015 (Prevention and Control, 2018) while the rate for HA-MRSA remains high in Southern Europe (Cassini et al., 2019). HA-MRSA strains are commonly linked with the severe type of pneumonia and sometimes bloodstream infection while CA-MRSA strains are associated with the infection of soft tissues and the skin (Cassini et al., 2019; Deleo et al., 2010).

1.6.2 Vancomycon-resistant enterococci

A common source of hospital-acquired infection is E. faecium and vancomycin-resistant strains are becoming more common (Lebreton et al., 2013). In the US the distribution of Enterococcus arisen in two distinct waves. In the 1980s, the first wave occurred, when the third generation of cephalosporin was introduced, resulting in the development of ampicillin and vancomycin-resistant E. faecalis (Murray, 1990). The second wave was thought to have expanded from the US to other areas of the world, influenced by vancomycin-resistant E. faecium (VREfm). An increase in VREfm prevalence among hospitalized patients has been observed in several European nations (Pinholt et al., 2015). The 47% of E. faecium in Australia's blood culture isolates were VREfm, which contributes to the vancomycin-resistant enterococci (VRE) incidence rate that is higher than that of many other developed countries (EFSA, 2015). VREfm clonal complex 17 (CC17) multilocus sequence types (ST) are presently responsible for a major load of hospital-acquired infections. The microbiome of the gut of the domesticated and wild kind animals contains a lot of these bacteria (Lee, Pang, et al., 2019; Marques et al., 2018). In Asia, Europe, South America, and Australia, CC17 strains have been linked to epidemics (Gao et al., 2018; Da Silva et al., 2012). Although the development of this complex is primarily ascribed to the zoonotic transmission of CC17 strains from animals to humans, fresh food had also been discovered to be a major reservoir (Lee, Pang, et al., 2019). Even though the transmission of strains CC17 within the community appears to be widespread, community-associated illnesses caused by these strains are infrequent. The requirement for isolation rooms, contact restrictions, and specialized room cleaning complicate the care of VRE-infected patients, adding to the expense and disturbance. Second-line antibiotic treatments (e.g., daptomycin and tigecycline) are used to treat serious infections, however, they are frequently linked with higher costs, lower effectiveness, and a higher risk of toxicity when compared to first-line antibiotic therapies’ cost, efficacy, and risk of toxicity (Prasad et al., 2012). The majority of studies have found a link between VRE infection and increased mortality, duration of hospital stay, and treatment expenses (Chiang et al., 2017), especially when VRE causes a bloodstream infection (Diazgranados and Jernigan, 2005).

1.6.3 Klebsiella pneumoniae

Cephalosporins and carbapenems classes of the antibiotic have usually been the main stay of treatments for the serious infection caused by the Enterobacterales, like that by K. pneumoniae, but efficiency has already been cooperated by the extensive acquisitions of the gene encodings enzyme, that is, extended-spectrum beta-lactamases (ESBL) and the carbapenemases, that can mediate particular resistances to these serious drugs (Paterson and Bonomo, 2005; Aslam et al., 2020a; Chaudhry et al., 2020). Increasing rates of mortalities, frequently exceeding 40%, had already been related to the severe infection caused by these carbapenem-resistant enterobacterales (CREs) (Tzouvelekis et al., 2012). Operative antimicrobials options are often missing, and the dealing typically needs reliances on the drugs having the risks of toxicities (e.g., polymyxins, aminoglycosides) or the other safety concern (e.g., tigecycline) (Kaewpoowat and Ostrosky-Zeichner, 2015). Carbapenem-resistant K. pneumoniae (CRKPs) strain has been the most clinically bulging CREs (Prevention and Control, 2018). The spread of these CRKPs in the Europeans has already been focused on the, directly and indirectly, patients to patients communications in the nosocomial setting, widely credited to ST15, ST101, ST258, and ST11 strain, along with ST258 derivatives ST512 (David et al., 2019). Global distribution of the CRKPs is illustrated by CRKPs clones ST307. ST307 clones had effectively dispersed across every main continent (Wyres et al., 2019). The recent news suggested that the AMRs, that is, hypervirulent K. pneumoniae (HvKPs) strain have also been emerging. In Taiwan, hvKPs cause as many arising cases of the necrotizing fasciitis as that of S. pyogenes and are also accompanied by high mortality rates, that is, 47.0% versus that of 19% (Cheng et al., 2012). One of the important laboratory features of K. pneumoniae K1 and K2 serotypes include the production of hypermucoviscous capsule (Li et al., 2014).

1.6.4 Acinetobacter baumannii

Infections of A. baumannii usually occur in patients who are hospitalized or in those patients who have substantial contact with the healthcare or clinical systems (Li et al., 2014; Khurshid et al., 2020c; Khurshid et al., 2019; Khurshid et al., 2020a). In US about a 50% rise in the frequency of hospital and community-acquired infections was observed between 1987 and 1996 in between July and October months (Mcdonald et al., 1999). Around 45% of A. baumannii isolates collected globally have been considered as MDR, which has 60% exceeding rates occur in US (Magill et al., 2014). In temperate climatic regions, A. baumannii isolates have usually been commonly increasing since the 1970s, a change chiefly assigned to environmental diligence mechanisms and the MDR progress (Harding et al., 2018). In tropical areas of Asia and Australia, community-acquired pneumoniae because of A. baumannii have been described in those individuals having a history of drug or alcohol abuse, levels for the MDR of A. baumannii have four times higher than those detected in P. aeruginosa and K. pneumoniae between 2011 and 2016 (Organization, 2014) The rates of isolation and identification of the A. baumannii isolate, that is, resistant to the carbapenems and β-lactam-classes of antibiotics has been enhanced by over the 30% globally (Xie et al., 2018b). The extent of the spread of the MDR and the carbapenems resistant to A. baumannii also known as CRAB isolates has greatly connected with the three worldwide clonal’s lineages, that is, CC3, CC2, and CC1 (Zarrilli et al., 2013; Khurshid et al., 2020b; Taj et al., 2020). CC1 is usually predominant international, while the CC3 and CC2 are extremely dominant in North America and Europe. CC79 and CC12 are also extremely dominant in South and Central America (Tavares et al., 2019). Due to the rise of pan drug-resistant isolates, last resort carbapenems and polymyxins classes of antibiotics have been no longer active and effective (Xie et al., 2018a; Khurshid et al., 2017).

1.6.5 Pseudomonas areuginosa

P. aeruginosa is a Gram −ve bacteria which a common human pathogen causing opportunistic infections frequently linked to severe respiratory tract infections in immunocompromised persons. P. aeruginosa is the cause of 10% of all hospital-acquired infections, it is also becoming frequently recognized as a cause of community-acquired infections. The ability of P. aeruginosa to continuously persist in the host and resist antibiotics is largely due to its repertoire of regulatory genes (which account for more than 8% of the 6MB genome) (Gellatly and Hancock, 2013). P. aeruginosa recently displayed intrinsic resistance against a wide range of antimicrobial agents and showed resistance against multiple classes of antibiotics. Globally, the patterns for P. aeruginosa AMR may vary considerably. The highest rate today for the AMR in P. aeruginosa arises in Central, South, and North America, Central, and Western Europe, China, India, and South Asia. The P. aeruginosa ST 175 and ST 235 had been investigated as high-risk dispersed worldwide clones and had remained a remarkable contribution to the hospital-acquired infection. Wide spread dispersal for P. aeruginosa resistance for last-resort, that is, carbapenem and the polymyxin-class antibiotic has been very well documented.

Hereditary or patients with chronic diseases of lungs like cystic fibrosis and bronchiectasis are the more prone to pulmonary infection, with sporadic exacerbation requiring hospitalized and intravenously antibiotic treatment, with a consequent risk of MDR selection (115). P. aeruginosa has been proven to survive for more than a decade in the lungs of CF patients (116). Humid conditions are favorable in the colonization of P. aeruginosa and so found in a variety of health care units, particularly in terms of chronics wounds, mechanical ventilation, or the urinary tract devices, where the formation of biofilms contributes to persistence, evade the immune system, and resistance to antimicrobial drugs.

1.6.6 Enterobacter species

In the intensive care units for the last 35  years, the Enterobacter aerogenes (that are named again as Klebsiella aerogenes) and the E. cloacae had shown a remarkable threat in the ward of neonatal patients mostly for those that depend on mechanical ventilators (Davin-Regli and Pagès, 2015). These two Enterobacter species have emerged as important clinical MDR pathogens in parallel epidemic waves. E. aerogenes was the most common cause of Enterobacter-associated hospital-acquired infections from the early 1990s until 2003, E. cloacae surpassed E. aerogenes as the more prevalent clinically investigated species of the genes around 2010. Other members of E. cloacae family, particularly Enterococcus hormaechaei are clinically important and can be difficult to distinguish at the species level using conventional phenotypic techniques (Mezzatesta et al., 2012; Annavajhala et al., 2019). MDR Enterobacter species have become an increasing factor for hospital-acquired infection. ST4 and ST93 of E. aerogenes in US have currently represented prevalent lineages that are associates with nosocomial infections (Malek et al., 2019). Recent data reveal that due to the development of nosocomial carbapenem-resistant E. cloacae ST178 and ST78 isolates (Gomez-Simmonds et al., 2018). Carbapenem resistance has spread directionally across the US (Sader et al., 2003). An estimated 99.9% of stains of Enterobacter were susceptible to the carbapenems prior to 2005 but resistance to the carbapenem has now been observed in all health zones of WHO (Thiolas et al., 2005). Furthermore, pan-drug-resistant E. aerogens have evolved, showing resistance to the antibiotic colistin, which is used as a last option for treatment. E. aerogens is capable of retaining subpopulations of colistin-resistant bacteria that are undetectable with existing diagnostic testing procedures, thus complicating the treatment of bacterial infections (Band et al., 2016).

1.6.7 Escherichia coli

One of the major causes of global burden for the bloodstream and the urinary tract infections in clinical settings as well as in communities is associated with antimicrobial-resistant E. coli AMR E. coli. However, the pathogen is still not fully considered as a member of ESKAPE pathogens (Cassini et al., 2019; Vandecraen and Chandler, 2017). While one of the common complications of UTI caused by E. coli is sepsis. Many clones (sequence types) of MDR uropathogenic E. coli with pandemic potential especially ST95 and ST131 are now disseminated globally (Schembri et al., 2015; Mathers et al., 2015). Consequently, in Australia from both urinary tract and bloodstream infections, MDR E. coli is a highly prevalent isolate (35). Throughout Europe, an increased rate of resistance against third-generation cephalosporins, aminopenicillins, aminoglycosides, fluoroquinolones has been noted. This increase in resistance is because of the ability of E. coli to acquire resistant genes from other drug resistance members of Enterobacterales through HGT 64. During the last decade, the emergence of Carbapenems resistant CRE E. coli in Europe raised concerns. However, this CRE E. coli is still under control for causing invasive infections (134). Additionally, in 2016 colistin and last resort polymyxin resistant isolates of E. coli were isolated in China (Liu et al., 2016). Resistance to antimicrobial in E. coli is presently among the most severe medical problems confronting both animal and human health. To avoid exacerbating such issues, institutions working on AMR policies, R&D, and monitoring must treat these bacteria as a significant public health problem.

1.6.8 Mycobacterium tuberculosis

Due to its airborne transmission, nomadic characteristics, and globalization, TB constitutes a great danger for communities around the world. The campaign launched by WHO in 2015, is to adopt strategies to confine the global threat of TB to just 5%–10% in mortality and prevalence respectively from 2035 (Johnson et al., 2017; Khan et al., 2016). The drug-resistant Mycobacterium tuberculosis especially those resistant to rifampicin and isoniazid are designated as MDR M. tuberculosis (MDR-TB) and are the leading cause of death due to (TB) (Paul, 2018). The isolates that showed resistance to rifampicin and isoniazid, which are drugs of first-line treatment are designated as MDR tuberculosis. While, isolates are resistant to first-line treatment drugs as well as from one among amikacin, kanamycin, or capreomycin the second-line treatment drugs and also from one of the fluoroquinolones are designated as extensively drug-resistant M. tuberculosis (Marks et al., 2014; Mullerpattan et al., 2019). An estimate by the WHO the cases of (TB) caused by MDR-TB increasing with the rate of 480,000 cases every year and among these cases, only 132,000 are reported worldwide. Additionally, the more serious threat is the increasing number of extensively drug resistance (TB) (resistant to multiple drugs) cases with a rate of 10% increase each year (World Health Organization, 2016 Update). Deaths in immunocompromised patients especially those infected with HIV are quite high. Among 1,450,000 deaths due to (TB) in 2018, it was estimated that 251,000 patients were HIV positive (Borisov et al., 2019). Due to its global dissemination, 1.7 billion of the world’s population is exposed to the bacterium M. tuberculosis which ultimately causes TB. Among this population, infection is developed in 5%–15% of the population (Houben and Dodd, 2016). As the cure rates against infection (TB) caused by MDR strains are very depressing, the concerns to public health are increasing with each day passed (Schrager et al., 2020) because there are extraordinary proportions of mortality (Chung-Delgado et al., 2015) and the astonishing cost for treatment of patients with the MDR TB (Marks et al., 2014; Mullerpattan et al., 2019). However, many highly effective TB vaccine candidates are now being tested in preclinical trials (Jeyanathan et al., 2015).

1.7 One health and antibiotic resistance

If you eat, you are involved in agriculture Wendell Berry. If I had only one hour to solve a problem, in attempting to define what the problem is I would spend up to two-thirds of that hour Finley and Ziobro. The global spread and the damage of antibiotic resistance are not only affecting humans but the environment and animal health too, which makes it a fundamental One Health issue (Robinson et al., 2016). Being a building block of One Health principle agriculture is always important in maintaining a balance between the health of soil, humans, and animals (Durso and Cook, 2019). To address the issue of AMR in the framework of the One Health approach the community is highly convinced to minimize the dissemination of ARGs to and fro the environment (Williams-Nguyen et al., 2016). The influx of genes, bacteria, and drugs into the environment from conventional or natural resources played a fundamental role in building up consensus and new knowledge in the domain of One Health (Sutherland et al., 2013; Sandberg and Lapara, 2016). Therefore, One Health can be defined as the study of interfaces between diverse environments from the interaction of the constituents in these interfaces to the consequences that they brought. Abruptly understanding the principal concept behind the One Health AMR can be the best example (Baquero et al., 2019). Describing the AMR through One Health the primary concern for human health is an infection caused by pathogens that acquire MDR genes and AMR in clinical settings is considered to be a direct consequence of AMR reservoirs in soil (Forsberg et al., 2012). However, the knowledge gap which still resides in the assessment of the links between the emergence of AMR and agroecosystems (Topp et al., 2018). Here the key players responsible for the dissemination of AMR genes are worth to be mentioned. The genes responsible for the resistance are particularly disseminated through mobile genetic elements (MGEs). Consequently, the emergence of AMR in One Health microbiosphere which include microbiotas of different environments like sewage, soil, water, human and animals is a result of bacterial species acquiring MGEs and getting integrated into these environments. While this emergence of AMR is dependent upon the network that linked all these biological, ecological and genetic entities (Baquero et al., 2019). While considering the interfaces, the communication networks between plants, human, and animal environments with the external environment are of fundamental importance in the One Health dimension (Abubucker et al., 2012; Adeolu et al., 2016). Also, the intensity of communication networks between the aforementioned environments and their microbiotas and the interspecies communication between these microbiotas is directly proportional to the dissemination of ARGs in this One Health microbiosphere. Furthermore, when describing the communication networks in the context of AMR globally prevalent MGEs plays defining role in the overall AMR burden (Baquero, 2004), which allows a space selection with varied levels. The selection is then a condemnatory element responsible for the success of the communication as it provided the interpretation for the transmitted message (D’costa et al., 2006). Well before the use of antibiotics, it was discovered that resistant genes for antibiotics were flowing among the members of Enterobacteriaceae by means of plasmids, transposons, or integrons, the current MGEs (Rowe-Magnus et al., 2001). While the rapid colonization of these MGEs with ARGs evolved as the result of anthropogenic antibiotic use and selective pressure that was exerted. This exploitation allows the communication networks to develop and leads to the spread of massage (antibiotic resistance genes) through MGEs which previously colonized at preantibiotic resistance genes (Baquero et al., 2019). The population and interconnectivity (potential for connections) of all such organisms are proportional to communication. This cohabitation of compact human populations and high densities of terrestrial vertebrate species (most with a greater incidence of microbiota merging), simultaneously occupying the same habitat, creates a considerable potential for recurrent biological interactions, notably microbiota integration (Ley et al., 2008). Here the important fact needed to be stated, accessory genomes as well as antimicrobial-resistant genes float in the same of the channels. The accessory genome contains the majority of genes responsible for sustainable interconnection between the environment and bacterial cells. This is because when a specific operon flows across bacterial species, the ARGs which are associated with that operon also migrate (Paquola et al., 2018).

1.8 Living with superbugs

Many research programs including (the development of new drugs) worth millions of euros had been initiated to improve human and animal health. However, the follow-up studies for these programs have reviled only a few of them has worth investing this huge amount. Due to lack of efficacy, nonselective toxicity, expensiveness, and phase two failure, there is an urgent need for new antibiotics. Also, many of the pathogenic bacteria causing life-threatening infections are now resistant to all known antibiotics and designated as (superbugs). The extensive and un-disciplined use of conventional antibiotics is one of the fundamental reasons for the emergence of these superbugs (Bravo et al., 2018). In many cases of invasive clinical procedures and during anticancer treatment MDR nosocomial infections are very frequent and the worst-case scenario is when their treatment leads to the selection of more AMR bacteria (Zaman et al., 2017). While copping up with a shortage of antibiotics and more severe kinds of AMR bacteria (superbugs) the previously known terms like preantibiotic era or dark horizon are now becoming old-fashioned (Chan et al., 2015). In 2016 antimicrobial-resistant bacteria and associated infections were designated as the leading threat to human health by the general assembly of health ministers of G20 countries (2016). Furthermore, one of the recent reports by WHO, claims about 50 million deaths by 2050 and some recent studies also augmented the previous knowledge by synthesizing new possible antibiotics (Kealey et al., 2017; Lin et al., 2018). Reports from the world’s renowned surveillance and research organizations including the CDC and WHO indicate the emergence of highly resistant strains around the globe with their uncontrollable dissemination. To efficiently reduce antibiotic abuse by increasing overall surveillance, an agreement had been taking place between 154 countries in 2018, however, later reports showed that un-prescribed selling of antibiotics is still very much uncontrollable. Consequently, there are increasing economic and health-associated burdens in many countries (Bravo et al., 2018; Phillips et al., 2004), The likelihood of AMR bacterium emergence is directly proportional to the antibiotics used on farm animals increases. In that context, a 2017 European Union report, commented on by the EMA, implied an undeniable correlation between overall antibiotic usage as well as the incidence of antimicrobial resistance in both humans and farm animals, resulting in recommendations for measures dedicated to the appropriate use of all types of drugs to minimize the severity of co-selection, that also takes place when the use of a single antibiotic result in the emergence of resistance to other types of drug (cross-resistances). Antibiotics fed to animals are considered a severe hazard that has been investigated, and the data available is staggering. Antimicrobial sales for cattle could have been collected in 38 countries and approximated in an additional 190. The worldwide use of all antibiotics in cattle was predicted to be 131,110 tons in 2013, with an expected increase to 200,235 tons by 2030 (Phillips et al., 2004). That offers some indication about how much stress is being imposed on bacteria, ultimately resulting in resistance selection in both ecosystems and animals. An estimate released by DC Offices, over half of all bacterial infectious illnesses may indeed be received from animals to human, including livestock, pets, and wildlife. Public health agencies and researchers from many areas are collaborating to answer fundamental issues about when, how, where, and why the bacterial infections are transmitted to people, with the goal of averting epidemic and pandemic outbreaks (Bravo et al.,