Antibiotic Resistance J Davies, University of British Columbia, Vancouver, BC, Canada
© 2013 Elsevier Inc. All rights reserved.
This article replaces the previous edition article by PM Hawley, volume 1, pp 74–76, © 2001, Elsevier Inc.
Glossary Antibiotic Antimicrobial produced by living organism (bacteria or fungi). Antimicrobial Synthetic or natural chemical substance that inhibits or kills microbes. Biofilm Aggregation of one or more class of microbe on a solid surface (e.g., a catheter). Fitness The ability of mutated microbes to persist under stressful conditions in infection. Gram test A chemical test that differentiates the two major classes of bacteria.
Antibiotic resistance (AR) has been known since the first dis covery of antibiotics. Since that time, it has flourished in the microbial population concomitant with the uncontrolled use of antibiotics in human health and in nonhuman applications such as in agriculture and animal husbandry. AR is widespread in all types of microbial disease – bacterial, viral, protozoan, and fungal. Despite 60 years of discovery research, currently, there is no resistance-free antimicrobial agent available that can be guaranteed to treat common bacterial, fungal, parasitic, or viral infections. In bacteria, AR arises in several different ways. In the first instance, certain bacterial species are intrinsically resistant to commonly used antibiotics, for example, the nosocomial Pseudomonad and Acinetobacter infections. In addition, many bacterial infections are caused when bacteria adopt different modes of growth; for example, they can adhere to tissue sites in the body to form biofilms, which are refractory to antibiotic action. However, the primary genetic mechan isms by which resistance becomes established in bacteria are by mutation and/or horizontal gene transfer (HGT). Mutations to AR often occur spontaneously during the course of treatment, when selection pressure is constant. The best (and most tragic) example is in the case of tuberculosis (TB) where the pathogen Mycobacterium tuberculosis rapidly acquires mutations to multiple drugs leading to multidrug resistant (MDR) or even extensively-drug-resistant (XDR) TB. In the latter case, the bacterium has mutated to reduced sus ceptibility to all the first-line TB drugs. M. tuberculosis has not been found to acquire resistance by HGT. Multidrug resistance is the rule and not the exception for the most common human bacterial pathogens. It is of interest to note that the most frequent mechanism of resistance is the ability to pump anti biotics out of the cell. HGT of antibiotic resistance genes was first reported in Japan in 1956; this is recognized as the most general mechan ism for the acquisition and spread of resistance associated with the clinical use of antibiotics. It can be safely assumed that widespread distribution of AR within mixed bacterial popula tions on a global scale is primarily due to HGT. Table 1
Brenner’s Encyclopedia of Genetics, 2nd edition, Volume 1
Horizontal (or lateral) gene transfer Passage of genes from one organism to another. Multidrug resistance Resistance to more than one class of antibiotic. Mutation Genetic alterations (DNA) that lead to a change in property such as resistance. Pathogen A disease-causing microbe. Plasmid Genetic element (DNA) that provides accessory functions (antibiotic resistance) to bacterial cells.
provides a list of some of the biochemical mechanisms of AR found in bacterial pathogens; some are due to mutation and others by HGT. The latter are always dominant characteristics. Nonetheless, various mutations are probably associated with most instances of AR, since the stable acquisition of plasmids by bacteria is frequently accompanied by mutations in the host that ensure stable maintenance of this additional genetic mate rial by the host. Other mutations may also ameliorate fitness defects in the pathogen. On a positive note, the identification of resistance plasmids in bacteria revolutionized the practice of bacterial genetics. The discovery of cross-species transformation methods, added to the availability of AR genes as dominant selective markers from the early 1970s, led to the development of recombinant DNA techniques and the birth of the biotechnology industry. Even the manipulation of eukaryotic cells with foreign DNA has been made possible using specific AR genes. Where do AR genes come from? The origins of transmissible antibiotic resistance genes are obscure, although there is circum stantial evidence that they arise from environmental microbial populations. In particular, these bacteria have mechanisms to extrude toxins; in addition, all bacterial strains known to pro duce compounds with antibiotic activity possess the so-called mechanisms of self-resistance. An excellent review of the AR genes from antibiotic-producing actinomycetes by Cundliffe and Demain lists AR mechanisms genes that appear to be asso ciated with natural antibiotic resistance in 100 or so different production strains. More recently, the powerful techniques of new-generation DNA sequencing methods and metagenomic analyses of the AR genes present in different environmental microbiome populations, such as soils and the human gastro intestinal tract, have revealed that putative or proto-AR genes are widespread in nature. Currently available sequence databases of AR genes list tens of thousands of AR gene homologs. However, it must be pointed out that that these are not all genuine AR genes and may well exercise different metabolic functions in their hosts in nature. In most cases, the connection between the potential AR genes and those found in bacterial pathogens is not proven: they may encode identical modes of action but
Antibiotic action and resistance mechanisms
βlactams (G+, G–)
Penicillins (ampicillin) Cephalosporins (cephamycin) Penems (meropenem) Monobactams (aztreonam) Gentamicin Streptomycin Spectinomycin (an aminocyclitol)
Hydrolysis Efflux Altered target
Vancomycin Teicoplanin Minocycline Tigecycline
Phosphorylation Acetylation Nucleotidylation Efflux Altered target Reprogramming of peptidoglycan biosynthesis
Phenicols (G+, G–)
Quinolones (G+, G–)
Pyrimidines (G+, G–) Sulfonamides (G+)
C1 metabolism C1 metabolism
Lipopeptides (G+) Cationic peptides (G+,G–)
Daptomycin Colistin Polymixin B
Cell membrane Cell membrane
Aminoglycosides (G+, G–)
Glycopeptides (G+) Tetracyclines (G+, G–)
Monooxygenation Efflux Altered target Hydrolysis Glycosylation Phosphorylation Efflux Altered target Nucleotidylation Efflux Altered target C O Lyase (type B streptogramins) Acetylation (type A streptogramins) Efflux Altered target Efflux Altered target Acetylation Efflux Altered target Acetylation Efflux Altered target Efflux Altered target Efflux Altered target ADP‐ribosylation Efflux Altered target Altered target Altered target Efflux
G+, active against Gram-positive bacteria (Staphylococci, Enterococci, Streptococci, etc.) G–, active against Gram-negative bacteria (Escherichia, Salmonella, Pseudomonas, etc.) Table provided by Dr Gerry Wright, McMaster University.
usually differ in other respects, such as DNA base composition and associated regulatory mechanisms. The evolutionary pathway(s) leading to the acquisition of functional AR genes by pathogens remains to be demonstrated. A well-characterized bacterial genetic system that may oper ate to capture proto-resistance genes from environmental sources is the integron. Such structures are present in many bacterial pathogens and their plasmids, the AR genes are found in clusters that are assembled by recombination at a single site, downstream of a strong promoter that controls the levels of expression of the resistance phenotypes (Figure 1).
Integrons encode multi-AR mechanisms active against a variety of different antibiotics. Infectious diseases, once thought to be under control because of the general availability of antibiotic treatment, have now become a threat to human, animal, and plant life worldwide. The spread of a multiplicity of AR strains by intercontinental travel has contributed to epidemics of AR bacterial infections across continents. For example, methicil lin (or multi-) resistant Staphylococcus aureus (MRSA) was rapidly disseminated to most countries of the world in the years following its identification in Europe and, as a result,
Integron class 1: Pc
5′ Conserved region Gene cassettes
3′ Conserved region
Figure 1 The structure of an integron. IntI 1: the integrase gene, responsible for the recombinatorial integration of new resistance cassettes. AttI and attC: recombination sites for the integration of new resistance cassettes. Pc: a strong promoter that ensures transcription of downstream cassettes. Gene cassettes: genes that encode resistance mechanisms to a variety of antibiotics. Qac,sul: conserved resistance functions.
this drug has become essentially useless for the treatment of hospital infections. A recent variant of MRSA known as com munity-acquired (CA)-MRSA has become widespread outside hospitals; this version of the pathogen is highly virulent and is readily spread by contact. In the case of Gram-negative pathogens, one class of resis tance enzymes, the extended spectrum β-lactamases called CTX-M, which determine resistance to a wide range of cepha losporin antibiotics, has been found internationally. In the past year, a new variant of this gene family, called NDM-1, first identified in pathogens in Asia, has now been found in Europe and North America. It is evident that antibiotic use for nontherapeutic purposes, such as growth promotion and prophylaxis in farm animals and agriculture, contributes to the global selection pressures for AR strains. There is good evidence that resistance to the anti biotic vancomycin, the antibiotic of choice for treating serious Gram-positive infections in humans, developed because of the extensive use of a related antibiotic in pig farming. The increased incidence of hospital infections by vancomycin-resis tant strains of Enterococci (VRE) and Staphylococci is responsible for significant increases in patient morbidity and mortality in intensive care units. What can be done to control antibiotic resistance develop ment? Given the current situation in Europe and North America where widespread AR is making a number of antibio tics obsolete, physicians are pressing for stricter controls on nonhospital use of antibiotics, better tracking of AR genes, and demanding that initiatives be introduced to encourage the pharmaceutical industry to strengthen their efforts to dis cover and develop new and potent broad-spectrum antibiotics. However, ensuring the long-term effectiveness of antibiotic treatment may require more draconian approaches before the situation comes under control. Moreover, to prevent the casual transmission of resistant pathogens, resistant or not,
good personal hygiene, with effective hand washing using plain soap and water cannot be improved upon!
See also: Biofilms; Fitness; Horizontal Gene Transfer; Mutation; Plasmids.
Further Reading Boucher HW, Talbot G, Bradley JS, et al. (2009) Bad bugs, no drugs: No ESKAPE! An update from the Infectious Diseases Society of America. Clinical Infectious Diseases 48(1): 1–12. Cundliffe E and Demain AL (2010) Avoidance of suicide in antibiotic-producing microbes. Journal of Industrial Microbiology and Biotechnology 37(7): 643–672. D’Costa VM, McGrann KM, Hughes DW, and Wright GD (2006) Sampling the antibiotic resistome. Science 311: 374–377. David MZ and Daum RS (2010) Community-associated methicillin-resistant Staphylococcus aureus: Epidemiology and clinical consequences of an emerging epidemic. Clinical Microbiology Reviews 23: 616–687. Davies J and Davies D (2010) Origins and evolution of antibiotic resistance. Microbiology and Molecular Biology Reviews 74: 417–433. Fluit AC and Schmitz F (2003) MRSA: Current Perspectives (ISBN 0-9542464-5-4). Wymondham: Academic Press. Gin AS and Zhanel GG (1996) Vancomycin-resistant enterococci. Annals of Pharmacotherapy 30: 615–624. Liebert CA, Hall RM, and Summers AO (1999) Transposon Tn21, flagship of the floating genome. Microbiology and Molecular Biology Reviews 63: 507–522. Liu B and Pop P (2009) ARDB – antibiotic resistance genes database. Nucleic Acids Research 37: D443–D447. Livermore DM, Canton R, Gniadkowski M, et al. (2007) CTX-M: Changing the face of ESBLs in Europe. Journal of Antimicrobial Chemotherapy 59: 165–174. Lu K, Asano R, and Davies J (2004) Antimicrobial resistance gene delivery in animal feeds. Emerging Infectious Diseases 10: 679–683. Ryan F (1992) The Forgotten Plague: How the Battle Against Tuberculosis was Won and Lost. Boston, MA: Little, Brown. So A, Furlong M, and Heddini A (2010) Globalisation and antibiotic resistance. British Medical Journal 341: c5116. Sommer MOA, Dantas G, and Church GM (2009) Functional characterization of the antibiotic resistance reservoir in the human microflora. Science 325: 1128–1131. The Lancet: Editorial (2006) XDR-TB – a global threat. Lancet 368(9540): 964.