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69 Current Drug Metabolism, 2017, 18, 69-77

REVIEW ARTICLE ISSN: 1389-2002 eISSN: 1875-5453

The Ever Changing Face of Antibiotic Resistance: Prevailing Problems and Preventive Measures

Current Drug Metabolism

Impact Factor: 2.847

The international journal for timely in-depth reviews on Drug Metabolism

BENTHAM SCIENCE

Hemlata1, Arif Tasleem Jan2,* and Archana Tiwari1,* 1

Centre for Research Studies, Noida International University, Gautam Budh Nagar, India; 2Department of Medical Biotechnology, Yeungnam University, Gyeongsan, 712-749, Republic of Korea Abstract: Background: Antibiotic resistance is a global problem that presents significant risk to human health. Driven by selective pressure of antimicrobial agents, spontaneous mutation, recombination and horizontal gene transfer events, inappropriate antibiotic prescribing and use outside healthcare settings has increased their impact on healthcare system. Increasing risk for human health lead us to study resistance development mechanisms, associated factors that increase dissemination of resistance genes along with information of imperative measures necessary to curtail the growing menace.

Pe N rs ot on fo al rD U is se tri O bu n tio ly n

Current Drug Metabolism

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ARTICLE HISTORY Received: June 27, 2016 Revised: August 15, 2016 Accepted: September 17, 2016

DOI: 10.2174/13892002176661610141633 24

Methods: In this article, we emphasized on the state of knowledge regarding imprudent use of antibiotics that act as promoters of resistance development. For this, literature based search for articles and entries related to antimicrobial resistance was done. With ample of data available, selected was performed for the epidemiological and clinical based study to curtail the facts present in these data sets so as to get accurate and important information.

Results: Resistance mediated by different determinants such as TEM, SHV, OXA and CTX-M, methods of mobilization that increase spread across species and as such failure to available treatment regimens was studied. Addition to detection methods, information of the inhibitors and natural substance useful in mitigating the effect of multidrug resistance was included to strategies the policies and plans for restricting their spread. Conclusion: As intervention to this growing problem, modified use of antimicrobial agents, employment of different formulations of herbs along with public health interventions in restricting antibiotic use, are believed to be of great help in restricting their dissemination and as such spread to non-pathogenic bacterial isolates.

Keywords: Antibiotic, bacteria, ESBL, multidrug resistance.

INTRODUCTION The term antibiotics, which means “against life”, are natural or synthetic organic molecules that are effective against microorganisms. They are used to treat the infections caused by bacteria and fungus along with some prophylactic use against viral diseases. However, exposure to an antibiotic naturally selects organisms with the genes of resistance necessary for their survival [1]. With this, selective pressure causes screening that allows resistant bacteria to thrive and the susceptible to die off. This selective condition favors the propagation of resistant strains following founder effect. As antibiotic resistance genes reside on transmissible plasmids, it readily facilitates their transfer across different ecosystem barriers. In the current day scenario, escalating problem of antibiotic resistance that substantially reduces the susceptibility of disease causing organisms to available consortium of drugs has increased the mortality rate up to a great extent [2]. Occurrence of resistance genes in bacteria has been reported far before the commercial use of antibiotics for infection control. Increased incidences of resistance genes that foster resistance development occurred through gene mutation, alteration in outer membrane permeability and porin functions, efflux pump system, mutations in the penicillin binding protein and more importantly through horizontal gene transfer [3]. Bacteria are now armored with wide defense mechanisms that promote their existence and perpetuation in new territories (Fig. 1). Over the years, increased incidences of resistance development among wide variety of organisms have finally emerged with progeny no longer susceptible to antibiotics [3]. Challenging infections coupled with the abandoned antibacterial

research and development have thrown us on back foot that compelled us to re-think about the measures required to control further spread of resistance. The recent appearance of opportunistic organisms exhibiting multidrug resistance is complicating the advances as they thwart available treatment regimes not only in hospitals but also in community settings. Because of these resistance factors, most of the presently available antibiotics have either showed reduction in their effectiveness or have become totally ineffective. Nowadays, we are facing a great threat of infectious disease caused by organisms such as Enterococci, Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter baumanii, that have acquired multi-resistant phenotype not to one, but to many different antibiotics; thereby making them difficult and, sometimes, impossible to treat. Adhering to these facts, the present study is an effort to bring all these problems on the same platform, so as to have information on the strategies that are needed to adopt in order to reduce the global burden of infectious diseases. MECHANISM OF ACTION Antibiotics have bactericidal or bacteriostatic mode of action where they completely kill the bacteria or just inhibit their growth. Mechanism of antibiotic action is always site specific or target specific. They generally act on major physiological processes like translation, replication, cell wall synthesis, etc. On the basis of target specificity, they are categorized into five different groups:

*Address correspondence to these authors at the International Research Professor, Department of Medical Biotechnology, Yeungnam University, Gyeongsan, 712-749, Republic of Korea; E-mail: [email protected] Centre for Research Studies, Noida International University; Tel: +919582649114; E-mail: [email protected]

Antibiotics Inhibiting Cell Wall Biosynthesis Peptidoglycan is the major component of bacterial cell wall. In the cell wall formation, cross linking between NAM (N-acetyl muramic acid) and NAG (N-acetyl glucosamine) units is achieved with the help of enzyme D-D transpeptidase or penicillin-binding pro-

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70 Current Drug Metabolism, 2017, Vol. 18, No. 1

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teins (PBP) [4-6]. Among different PBPs, PBP-1 is involved in the peptidoglycan synthesis, PBP-2 (also known as carboxypeptidase) hydrolyses the dipeptide between D-alanine residues and thereby cause cross linking between NAM and NAG; and PBP-3 (an endopeptidase) is engaged in the septum formation between the cells. Antibiotics such as -lactams dissuade cell wall biosynthesis as they hold analogue property similar to D-alanyl-D-alanine structure. Having high structural similarity, PBPs introduce -lactam at the place of D-alanyl-D-alanine that led to the inhibition of transpeptidation [7]. -lactams inhibit transpeptidation reaction of NAM and NAG by targeting the function of transpeptidases. Sulfonate group of -lactams reacts with serine residue of transpeptidases that lead to production of inactive acyl enzyme [8]. Glycopeptides such as vancomycin that targets the D-alanyl-D-alanine moiety of peptidoglycan blocks transpeptidation. They produce their effect by causing osmotic imbalance that causes death to bacteria [9].

Antibiotics Inhibiting Protein Synthesis Antibiotics have yielded significant results in reducing the bacterial burden by successfully competing through interference in the protein synthetic machinery [10, 11]. Majority of the drugs that target larger ribosome subunit have been found effective by causing structural rearrangements. Tetracycline disturbs A-site on the larger subunit of ribosome, thereby prevents binding of aminoacyltransfer tRNA to the ribosomal A-site [12]. Alongside, several others such as aminoglycosides have been found interfering with the smaller subunit. Disrupting smaller ribosomal subunit results in misreading of the genetic code by tRNA that lead introduction of the wrong nitrogenous base pairs. In a similar fashion, macrolides, chloramphenicol, lingosamides and pristin binding to 23S rRNA also interferes with the protein synthetic machinery. Macrolides have both bactericidal and bacteriostatic activity. They deter function of peptidyl transferase, thereby triggers shifting of peptidyltRNA from A-site to P-site so as to prevent formation of peptide bond. Additionally, fusidic acid have been found preventing dissociation of GDP and elongation factor-2 complex, while as mupirocin prevents isoleucyl-tRNA synthetase that catalyze formation of isoleucyl-tRNA, thereby thwarting incorporation of isoleucine to peptide during protein synthesis. Antibiotics Inhibiting Folate Synthesis Folic acid is a water-soluble vitamin required for growth by both bacterial and mammalian cells. Besides acting as essential component in the synthesis of purines and pyrimidines, it is required for maintaining the cell wall integrity [13]. As animals and humans are unable to synthesize folate, it is acquired through the diet. Using dihydropteroate diphosphate and para-aminobenzoic acid as precursors, enzyme dihydropteroate synthetase (DHPS) catalyzes their conversion to dihydropteroic acid. Sulfonamides that target para-aminobenzoic acid are bacteriostatic in nature [14, 15]. Inhibition of bacterial growth results from the formation of inactive

folate-like analogues. Sulfamethoxazole inhibits the reaction by acting as a competitive inhibitor of dihydropteroate [13]. Further dihydrofolate reductase convert dihydropteroic acid to dihydrofolic acid, which is an intermediate of folic acid (Fig. 2). This catalysis is restrained by a competitive inhibitor trimethoprime (TMP). Antibiotics Inhibiting DNA/RNA Machinery Replication and transcription are the essential processes of all living organisms. Bacterial DNA-dependent RNA polymerase (RNAP) mediates the transcription cycle and represents a major point of regulation for prokaryotic gene expression. Of the different polypeptide subunits (III), only one of these sites on RNAP has so far been exploited in antibacterial chemotherapy. Rifampicin targets -subunit of RNA polymerase thereby interferes its binding to the DNA. As RNA polymerase became unable to read the genetic information coded by DNA, it prevents transcription of DNA [16]. With respect to replication, DNA gyrase controls the topological state of DNA in the bacterial cell by introducing negative supercoils into the molecule. This indispensable nature of gyrase and the absence of a direct counterpart in mammalian cells, make DNA gyrase an ideal bacterial drug target. Fluoroquinolones restrain the function of DNA gyrase in gram negative and topoisomerase IV in gram positive bacteria by forming complex with ssDNA. Quinolones such as ciprofloxacin have been found capable of interfering with the DNA topology by targeting DNA gyrase, thereby hindering negative super-coiling of DNA.

DRUG RESISTANCE DETERMINANTS AND RESISTANCE COMPLEXITY Resistome refers to collection of all antibiotic resistance genes in microorganisms from both pathogenic (disease causing) and nonpathogenic (non-disease causing) bacteria [17]. In the prevailing situation, a large number of bacteria have even developed resistance not only to different drugs but also to several potent inhibitors that ultimately cause high rate of mortality [18, 19]. With this, Extensively Drug Resistant (XDR) bacteria have emerged as more severe to combat than Multi Drug Resistant (MDR) bacteria. Recent appearance of XDR in mycobacterium has been found imparting resistant against rifampicin, isoniazid, fluroquinolones, injectable amikacin, kanamycin and capreomycin. According to WHO, a person that suffers infection from MDR-TB, has more than 50% possibility to develop XDR-TB [20]. In the recent years, a more serious concern has appeared in the form of emergence of Pan Drug Resistant (PDR) phenotype among different groups of bacteria. These findings highlight the grave concern regarding the increasing problem of antibiotic resistance. On adopting guidelines framed by the European Centre for Disease Prevention and Control (ECDC) and the Centre for Disease Control and Prevention (CDC), the term MDR was applied to bacteria exhibiting non-susceptibility to at least one agent in three or more antimicrobial categories, while XDR exhibits non-susceptibility to at least one agent in all except

Antibiotic Resistance: A Journey from Success to Failure

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from the cytoplasm [27]. They are categorized into five different classes: ATP-binding cassette transporters (ABC), Major facilitator transporters (MFS), Multidrug and toxic compound extrusion transporters (MATE), Small multidrug resistance transporters (SMR) and Resistance-nodulation-division (RND) type transporters.


two or fewer antimicrobial categories, and PDR exhibits nonsusceptibility to all agents in all antimicrobial categories. Of the different resistance determinant acquisition modes that operate in bacteria at the genetic level, the most common ones contributing significantly to the resistance development includes conjugation, transduction and transformation. Compared with determinants located on the chromosomes, those located on the extra chromosomal DNA i.e. plasmids, have resistance gene referred to as Rgene. R-gene transfer occurring with bacterial reproductive methods led to easy transfer of resistance determinants as part of spread of resistance to other members in a bacterial community. Although majority of microorganisms have become resistant by acquiring resistant determinants, organisms like methicillin resistant Staphylococcus aureus (MRSA) acquire resistance through mutations. A mutation may substantially increase the lethal concentration of a particular antibiotic, thereby impairing the available treatment [21]. Multiple mutations play a major role in chromosomal borne resistance development [22]. Integrons and transposons illustrate this type of resistance mechanism. Integrons: Integrons are the mobile genetic elements located on plasmids and transposons. Integron confers MDR and virulence phenotype due to presence of gene cassette at recognition site. Bacteriophages are the natural vector that transfer gene cassette to other bacterium and led to spread of resistance. Transposons: Transposons are the DNA sequences or genes which frequently change their position in genome. Staphylococcus aureus are fluoroquinolones resistant due to presence of gene gyrA and grlA [23]. Together, plasmids, integrons and transposons led to transmission of resistance through a common mechanism referred to as horizontal gene transfer (HGT). CTX-M-15 that was mainly detected in the clinical sample of E.coli, has now been reported in E.coli intriguing clone ST131. It is located on the mobile IncFll plasmids in association with operon genetic element IS26. Spread of both ST131 and IS26 make the organism MDR [24].

MECHANISM OF RESISTANCE DEVELOPMENT Resistance to different classes of antibiotics is achieved through various mechanisms particular being drug efflux, target modification, change in membrane impermeability achieved through mutation and enzyme inactivation (Fig. 3). DRUG EFFLUX Bacterial pathogens have acquired multidrug resistance by enhancing the functioning of active efflux pumps [25]. Efflux pumps are energy dependent active transporters associated with xenometabolism of antibiotics, toxic waste disposal and different resistance mechanisms [26]. The energy mediated efflux is the more powerful strategy developed by bacteria. AcrAB-TolC is a multidrug resistant pump. In E. coli, periplasmic linker AcrB combines with the Tol C channel of outer membrane to makes a continuous passage to get rid of the effect of tetracycline by expelling it

ATP-Binding Cassette (ABC) Transporters ABC transporters are energy mediated efflux pumps that hydrolyze ATP in expelling substances out of the cytoplasm against their gradient. ABC transporters are composed of two domains; a nucleotide binding domain (NBD) and a transmembrane permease domain (TPD). Both domains unite together to form a complete continuous extrusion system. With wide substrate range, they are involved in multiple physiological processes such as xenobiotic metabolism, expulsion of cellular metabolic wastes, bacterial pathogenicity and bacterial immunity. These pumps are found in all life domains [28]. LmrA was the first discovered ABC type efflux pump in Lactococcus lactis. MacAB (prior known as YbjYZ), a macrolide-specific ABC transporters found in E. coli is associated with the expulsion of macrolide and erythromycin. Major Facilitator Superfamily (MFS) Transporters MFS is one of the largest groups of secondary active transporters that play pivotal role in multiple physiological processes. Holding high degree of conserveness from bacteria to humans, they represents largest collection of structurally related membrane proteins that transport a wide array of substrates including ions, carbohydrates, lipids, amino acids, peptides, nucleosides, and other small molecules across bio-membranes [29-31]. Based on phylogenetic analysis, postulated substrate specificity and expected transport mode, they are sub grouped into 74 sub-families [31]. One remarkable characteristic of the MFS is the high sequence variety within the superfamily. The sequence identity ranges around 12–18%, but regions of functional similarity (e.g., substrate- or -binding sites) align for only very closely related MFS transporters [32, 33]. A hydrophobic amino acid content of 60–70% of most MFS members, high -helix content and the inherent symmetry of the proteins with regard to helix kinks and bends provides non-specific overlapping of residues and probably accounts for the reported similarities [34]. Despite intense investigation, only seven MFS proteins from six subfamilies have been structurally elucidated. These structures were captured in distinct states during a transport cycle involving alternating access to binding sites from either side of the membrane. MFS transporters are tripartite complexes whose function is well established for drug efflux across bacterial membrane. In bacterial community, nearly 25% efflux pumps that are of MFS type consist of water loving core surrounded by12 transmembrane helixes [33]. Lactose permease (Lac Y) gene of E. coli is the most common example of MFS type pump; catalyzing active transport of Lactose and H+ ions along concentration gradient across the bacterial membrane [34]. Coupling between sugar and H+ translocation in LacY involves uphill transport of sugar (against its concentration gradi-


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ent) coupled with the downhill H+ influx (thermodynamically favored movement).

Resistance-Nodulation Division (RND) Type Transporters RND type transporters (also known as tripartite efflux) are formed of domains belonging to inner membrane protein, outer membrane protein and membrane fusion protein. All three proteins form a continuous channel that functions as H+ antiporter, extrude the chemotherapeutics and drugs. RND type AcrB transporters that form tripartite with membrane fusion protein (MFP) and outer membrane protein/channel (OMP) TolC is associated with expulsion of antibiotics like tetracycline, chloramphenicol, -lactams, SDS, lipophilic ligands fatty acids and toxic waste from the cell. The expression of RND type MexXY efflux of P. aeruginosa that function via AlgU dependent pathway, shows elevated expression in response to ribosome-targeting antibiotics as a mode to save the bacterium [37]. Similarly, the stress of membrane damaging agents such as hydrogen peroxide and nitric oxide enhance the levels of MexEF-OprN transporter, which protect the cell from their damage [38].

and fatty acids and as such makes it more fit to colonize human intestines [39]. Phagocytosis: when pathogen enters inside the eukaryotic cells, it triggers the non-specific immunity. They cause infection through interference with reactive oxygen species (ROS) and reactive nitrogen spices (RNS) to defend itself from phagocytosis. SoxRS gene expressions in E. coli enhance the function of AcrAB efflux (RND type) and as such saves bacterium from the oxidative stress generated by host innate immune system [40]. Quorum sensing: Quorum sensing is the communication system between the bacterial communities. It modulates the expression of genes based on cell-density to make them more fit to their environment. Quorum sensing or bacterial talk is mediated by auto-inducers [41]. These self-produced communicating extracellular macromolecules such as N-acyl homoserine, cause pathogenicity by increasing the concentrations of autoinducer (AIs) that activate transcriptional factors or synthesis of R-protein. In turn, R-proteins elevate the expression of genes that increases biofilm synthesis. Quorum sensing in P. aeuoginosa promote the production of alkaline protease elastase (las) and rhamnolipid (rhl), thereby results in MDR biofilm and toxic protein production. In humans, increase in P. aeuoginosa biofilm virulence cause respiratory tract, burn wound infections and keratitis [42]. Biofilm forming bacteria such as Pseudomonas, Listeria, Bacillus, Salmonella and E. coli induce “Delayed Antibiotic Diffusion” into biofilms and as such makes the successful therapies challenging. Actually, a biofilm is an association of different species closely intimated by a slimy substance composed of saccharides. MexAB-OprM and pmr-mediated mutation in the lipopolysaccharide boosts P. aeruginosa biofilm to tolerate colistin, tobramycin, gentamicin and ciprofloxacin. Similarly, yhcQ gene in E.coli contributes to the biofilm-specific penicillin G resistance [43].

Function Attributed to Efflux Pumps • Host colonization and virulence: MDR efflux pumps that affect host-parasite specific interactions, helps bacteria to withstand human physiological stimuli such as stress signals, colonization, pathogenesis and cellular communications. RND type AcrB transporters save E.coli from high intestinal concentration of bile salts, hormones

Target Modification Spontaneous mutations that results in the modification of target sites, make bacteria resistant against antibiotics. Antibiotics such as streptomycin and erythromycin act on the translational machinery by binding to ribosomes. However, modification of the S12 protein of the 30S subunit makes it resistant to streptomycin. In a similar way, a mutation in L4 or L12 proteins of 50S ribosomal subunit

Multidrug and Toxic Compound Extrusion (MATE) Transporters MATE type transporters that act as H+ and Na+ antiport exchanger, provide resistance to toxic cationic drugs such as fluoroquinolones. They are found in all domains of life [35]. MATE transporters require energy sources in the form of PMF (proton motive force) and Na+ ion gradient. Although they resemble with the RND pumps in functions, they are quite different from them. Small Multidrug Resistance (SMR) Transporters SMR transporters are plasmid or chromosomal encoded proteins associated with the integrons. They transport neutral and negatively charged ions across the membrane. The smallest secondary efflux pumps are made up of approximately 107 amino acids. They are further divided into three subclasses: small multidrug pumps, paired SMR proteins and suppressor GroEL mutant protein [36].

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makes it resistant against erythromycin. Mutation in -subunit of RNA polymerase reduces the effect of rifampicin against Mycobacterium tuberculosis [16]. Similarly, mutations in the dhfr gene responsible for the production of enzyme dihydrofolate reductase, make bacteria resistant to trimethoprim in the case of S. aureus [44] and S. pneumoniae [45]. Additionally, point mutations in the chromosomal mediated fusA gene encoding EF-G makes S. aureus and staphylococci resistant to fusidic acid [46, 47]. This type of resistance spread to other bacteria via plasmids, transposons and integrons results in the buildup of resistance in the bacterial communities [48]. Membrane Impermeability

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CTX-M Type CTX-M are serine -lactamases with cefotaximase activity. They were firstly identified in Munich (Greek patient) thus derive their name as such. CTX-M -lactamases belong to Bush’s group 2be and Ambler’s class A in classification system [58]. So far 166 variants have been reported (www.lahey.org/studies). O n the basis of diversity and origin, CTX-M-type -lactamases are subdivided into five clusters: CTX-M-1, CTX-M-2, CTX-M-8, CTX-M-9 and CTX-M-25. CTX-M-15 is reported to have high prevalence rate followed by CTX-M-14 [59-61]. Recently, CTX-M-152 was also reported to have high prevalence among aquatic habitats from India [62]. OXA Type OXA type ESBLs are named after oxacillinase activity (enzymes that hydrolyze oxacillin and cloxacillin) [54]. OXA ESBLs are frequently detected in P. aeruginosa [63]. They are poorly inhibited by clavulanic acid. The prevalent OXA variants include OXA- 10, OXA-20, OXA-22, OXA-24, OXA-25, -26, and -27, and OXA-30 [64].


Impermeability is the prevention of flow within the membrane. Reduction in the bacterial membrane permeability results in cross resistance towards various families of antibiotics. In Pseudomonas aeruginosa, mutation in outer membrane D2 protein (opr D2) results in reduced permeability towards imipenin, while in OprD porin gene reduces the uptake of carbapenems [49]. Similarly, mutations in RpoB gene make bacteria resistant to rifampicin by causing change in the amino acid sequence of -subunit of RNA polymerase [50]. In absence of OmpA and OprF proteins having pore forming properties, Pseudomonas aeruginosa exhibit distorted shape and shows decrease in permeation to antibiotics [51]. The esterification in the lipid A phosphate moiety of E.coli results in reduced sensitivity of compactly arranged LPS layer towards polymyxin B and other cationic agents. Due to decrease in negative charge that reduces sensitivity of the bacterium, S. typhimurium becomes resistant towards cAMPs and survive inside the macrophages of the host [52].


Enzymatic Inactivation

-lactamase, an enzyme produced by both Gram-positive as well as Gram-negative bacteria, convert penicillin to therapeutically inactive compound, penicilloic acid. Penicilloic acid targets the proteins and acts as a hapten to initiate immune reaction. Though production of enzyme is inducible in Gram-positive bacteria, it is reported as constitutive in Gram-negative bacteria. Production of -Lactamases

-lactamase enzymes denotes extended spectrum of activity against third generation antibiotics. They are classified either according to Ambler classification based on protein homology or similarity of enzymes and/or by Bush–Jacoby–Medeiros classification based on functional properties of enzymes, such as substrate specificity and nature of inhibitor [53, 54]. According to Ambler classification, -lactamases of class A, C, and D are serine lactamase and class B as metallo -lactamase. SHV Type The plasmid mediated SHV are sulphydryl variable enzymes. Their serine and lysine residues attribute to hydrolytic activity against ceftazidime and cefotaxime. SHV-1, an enzyme universally found in K. pneumonia that shows resistance against ampicillin, tigecycline and piperacillin [55], increases sensitiveness against oxyimino cephalosporins [56]. In blaSHV, a single replacement of serine at position 238 with glycine, make them ESBLs. TEM Type TEM identified in Greek patient Temoneira, was first reported in 1965 in E.coli. TEM-1 is universally found in Gram negative bacteria: H. influenza and N. gonorrhoeae. TEM variants hydrolyze first generation cephalosporins. TEM-1 is considered as the ancestor of TEM-2 having a single amino acid change [57]. Though changing the isoelectric point from PI 5.4 to 5.6, their catalytic activity was found to remain same for the substrate.

Minor ESBLs Some other importantly described ESBLs include PER, GES, VEB, BES, CME and SFO [65]. All these enzymes have 40-50% homology with each other and have rare occurrence [66]. PER Type PER type ESBL first identified in Pseudomonas in 1991, were found to provide Extended Resistance, and hence named PER. The PER-1 -lactamase is the endemic of Turkey. Though, PER-1 type ESBLs provides resistance against penicillins, they retain sensitivity to cephalosporins and clavulanic acid [67]. PER-2 detected in K. pneumoniae, vibrio cholerae has nearly 86% homology to PER-1 [68]. GES type These Enzymes belong to ESBL class A [69, 70]. They are named as they were first identified in Guyana patient suffering from K. pneumoniae infection. GES-1 detected in neonatal patients showed migration from Guiana (French) to France via, K. pneumoniae species. GES-1 is resistant against penicillins and first generation cephalosporins. However, they are sensitive to cephamycins, carbapenems, and lactamase inhibitors. VEB Type Though, VEB-1 was first found in E.coli of a Vietnamic patient, it was later on also found in a patient from Thailand that suffered P. aeruginosa infection. VEB are plasmid as well as integron mediated ESBLs [71-73]. VEB are resistant to cephalosporins and aztreonam, but sensitive towards inhibitors. CME Type CME-1 was isolated from Chryseobacterium meningosepticum and hence named CME. They are also found in non- fermentative Gram negative rods [74]. BEL Type BEL-1 was first identified in Belgium in 2005, hence named as such. They belong to Ambler class A and have integron cassette. BEL- 1 significantly hydrolyses most of cephalosporins, aztreonam and tazobactam [72]. These are sensitive to clavulanate, cefoxitin, monalactam, and imipenem.

BES Type BES type ESBLs were first identified in Serratia marcescens from Brazil in 1966. BES type ESBLs shows activity against cefotaxime and ceftazidime. These are inhibited by clavulanate [75].


TLA Type They were first identified in Tlahuicas (Indian tribe) in 1991; hence named TLA. After that, it was also detected in Mexican patient in 1993 [76, 77]. They belong to Ambler class A -lactamase. TLA type ESBLs are resistant to cephalosporins while susceptible to penicillin. SFO Type They were first identified in Serratia fonticola in 1988 and hence named SFO. They are chromosomal encoded as well as plasmid mediated. SFO belong to ST11 clone. SFO-1 shows resistance against third generation cephalosporins and aminoglycosides and are co-transferred with aac(6)-Ib-cr gene.

they create a long term association with host or choose lysogenic life cycle. They utilize the host machinery for their use by integrating their genetic material into the host genome. However, sometimes after a long period of infection, they kill the bacterium by lytic life cycle e.g., lambda phage [87]. Lytic Phages or Virulent Phages Owing to their lytic mode, they represent true phages that are used in available bacteriophage therapies. Bacteriophage kills bacteria by liberating the viral particles in to the extracellular environment of the host cell [88]. They do not create imbalance with microbes of body’s own micro biota [89]. Although phage therapy seems as an alternative of antibiotics, it is still a matter of controversy. e.g., Phage Ø9882 having lytic activity against E. coli 9853. Though it represents a new approach in medical advancement, the therapy has been found to show a synergic effect with antibiotics. The therapy produces no allergic reactions. Time and cost is comparatively shorter than antibiotics. However, as part of disadvantage, phage-bacteria specificity demands precise molecular, behavioral and target selection. It alters host metabolism because of choice to adapt lytic or lysogenic life cycle. Phage-bacteria specificity is narrow as bacteria have different strains. In this case, only antibiotics represent more suitable partner that act against wide range of bacteria.


Detection of ESBLS Producers There are mainly two methods that are commonly employed in the detection of ESBLs.

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Phenotypic Method In this method, ESBL detection guidelines published by clinical and laboratory standards institute (CLSI) agency of USA and health protection agency (HPA) of UK are followed. The main principle of these guidelines is that ESBLs hydrolyze the valuable cephalosporins representing third generation antibiotics. In this method, inhibitors like clavulanate, sulbactam and tazobactam are used in combination with antibiotics. Confirmatory test is done with both cefotaxime + clavulanate (antibiotic and inhibitor) having concentration of 30 mcg. Genotypic Method PCR detection assay undoubtedly plays an important role in the detection of ESBLs. PCR assay requires primers to amplify universal DNA sequences. Different PCR types such as duplex PCR, multiplex PCR, real-time PCR, pyrosequencing and RT-PCR are used in the conformational assay of ESBL detection.

PREVENTIVE STRATEGIES Use of ESBL Inhibitors Inhibitors are substances which slow down enzymatic activity. Their combination with antibiotics shows synergistic effect that lead to decrease in MICs [78, 79]. A good inhibitor; binds at active site in irreversible manner, is required in low concentration and perform its affects without any side effect on the host (Bush, 1988). Inhibitors such as clavulanic acid, tazobactam and sulbactam (also called suicide inhibitors) are effective against organisms having determinants belonging to class A -lactamases such as CTX-M [80-82]. Clavulanic acid isolated from Streptomyces clavuligerus, is the first -lactamase inhibitor used in clinical purposes. Sulbactam and tazobactam are pharmaceutically designed penicillin sulfonates. Their supplementation with antibiotics led them to bind to active sites of enzymes in irreversible manner that disturbs their function [83, 84]. Piperacillin in combination with tazobactam was found exhibiting bactericidal activity against both aerobes and anaerobes [85]. All three -lactamase inhibitors show structural similarity with the penicillin. However, CTX-M-type -lactamases are better inhibited by tazobactam compared to sulbactam and clavulanate. Bacteriophage Therapy The viral parasites of bacteria are known as bacteriophages or hyperparasite. Hyperparasites have narrow range of specificity to kill bacteria. The target specificity of bacteriophage makes the therapy more suitable to treat bacterial infections [86]. Bacteriophages are mainly divided into two categories. Temperate Phages Temperate phages have either lytic or lysogenic life cycle depending on the host condition. Usually when host has slow growth,

Natural Products as Adjuvant to Antibiotics Allicin, a thiosulphate compound of Allium sativum that exhibit antimicrobial properties similar to -lactams antibiotics, was found to dissuade major processes like replication, transcription and translation in MDR organisms [90]. Its combination with vinegar show synergic effects against MDR bacteria (E. coli and MRSA), fungi (Candida) and protozoans like Giardia, Entamoeba histolytica, Trypanosomes and Leishmania [91]. Root extract of Coleus forskohlii, an aromatic herb belonging to family Lamiaceae, proved a better remedy against urinary bladder infections caused by multidrug resistant E.coli [92]. It produces its effect by inhibiting (GalP) Galactose-H+ symport transporter of E.coli [93]. Coriander oil has exhibit antibacterial activity against infection caused by MDR E.coli, Staphylococcus, K. pneumoniae, Salmonella, and Vibrio cholerea [94]. Azadirachtin, a versatile alkaloid of margosa is used to treat urinary infections caused by E.coli [95, 96]. It has antibacterial properties against S. mutans and S. faecalis and as such is used to control the respiratory disorders in children [97]. Having maximum activity against S. mutans, S. salivarius, S. mitis, and S. sanguis, it is used in overcoming dental problems caused by them. Gallic acid, a potential bioactive compound of Terminalia chebula exhibits broad spectrum activity against both gram negative and positive bacteria. It acts effectively against metallo-lactamases (MBLs) producing Acinetobacter baumannii [98]. It also exhibit antibacterial properties against Helicobactor pyroli, methicillin resistant Staphylococcus aureus and Clostridium perfingens [99, 100]. Syzygium aromaticum is evergreen plant belonging to Myrtaceae family. The essential oil of Syzygium aromaticum i.e., eugenol, exhibits broad spectrum activities Lactobacillus, E. coli and S. enterica [101, 102]. It also controls the spoilage food borne bacteria such as S. aureus, P. aeruginosa and E. coli [103]. Similarly, ginger, a perennial herb belonging to family zingiberaceae, is used to treat the infections caused by E.coli [104]. The rhizome of ginger exhibits antibacterial properties against multidrug resistant pathogens such as S. pneumoniae, H. influenzaeand S. aureus [105]. CONCLUSION Resilience of prokaryotes to antibiotic stress has contributed significantly to escalating burden regarding control of infectious diseases. Resistance to antibiotics occurred either by acquisition of resistance determinants or by mutations and ended with enrichment


Table 1.


A detailed information regarding ESBL inhibitors. Inhibitors with antibiotics

Brand Name

Antibiotic

Inhibitors –Action

Piperacillin-tazobactam

Zosyn

Penicillin type antibiotic.

Tazobactam show synergic effect with antibiotic and inhibit the bacteria from inactivating the drug

Ampicillin-sulbactam

Unasyn

Semisynthetic penicillin

Increases the efficiency of antibiotics

Amoxicillin-clavulanate

Augmentin, Augmentin

-do-

(In 1981 used in the U.K and in 1984 in U.S)

ES-600, Augmentin XR

Binds to the serine residues of the active site of the -Lactamase

Ticarcillin-clavulanate

Timentin

carboxypenicillin

-do-


(In 1983 used in U.S)

in the use of antibiotics as a strategy to treatment of infectious diseases. This enhancement in the use of antibiotics facilitated development of resistance mechanisms against the weaponry once employed for infection control. As the treatment of infectious diseases is compromised with available drug regimes, emergence of highly resistant bacteria resulted in huge loss of human asset. Fallout regarding misuse of antibiotics, their spread to wider community members of bacteria makes their treatment almost impossible. Representing an alarming situation in the current day scenario, collaborative efforts of all applied science fields is required in order to have a conscience of what is needed as part of global surveillance and infection control. Uprising problem of antibiotic resistance that represents an apocalyptic scenario needs proper and timely addressable strategies. As the available antibiotic regimes has lost their efficacy, it seems essential to create a robust and sustainable antibacterial research strategies in order to keep pace with the demand of global healthcare settings. Representing a great challenge, control of antimicrobial resistance needs steady supply of newer antibiotics along with other inhibitory substances that can adequately address the resistance concerns in order to curb the menace of increased drug resistance. Though available inhibitors and newly developed therapies has proved a boon in the control of infectious, exploring the hidden qualities of naturally occurring herbs is needed as a suitable additive strategy to combat the menace of MDR organisms and ESBLs.

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CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest.

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ACKNOWLEDGEMENTS We are greatly grateful to all our colleagues who help us to complete this review.

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