Cell Magazine 22 March 2007
Michael N. Alekshun and Stuart B. Levy
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Center for Adaptation Genetics and Drug Resistance, Department of Molecular Biology & Microbiology and Department of Medicine, Tufts University School of Medicine, Boston, MA 02111, USA
Available online 22 March 2007
Treatment of infections is compromised worldwide by the emergence of bacteria that are resistant to multiple antibiotics. Although classically attributed to chromosomal mutations, resistance is most commonly associated with extrachromosomal elements acquired from other bacteria in the environment. These include different types of mobile DNA segments, such as plasmids, transposons, and integrons. However, intrinsic mechanisms not commonly specified by mobile elementsÃ¢â‚¬â€such as efflux pumps that expel multiple kinds of antibioticsÃ¢â‚¬â€are now recognized as major contributors to multidrug resistance in bacteria. Once established, multidrug-resistant organisms persist and spread worldwide, causing clinical failures in the treatment of infections and public health crises.
Ã¢â‚¬Å“There is probably no chemotherapeutic drug to which in suitable circumstances the bacteria cannot react by in some way acquiring Ã¢â‚¬ËœfastnessÃ¢â‚¬â„¢ [resistance].Ã¢â‚¬Â
Ã¢â‚¬â€Alexander Fleming, 1946
Efforts aimed at identifying new antibiotics were once a top research and development priority among pharmaceutical companies. The potent broad spectrum drugs that emerged from these endeavors provided extraordinary clinical efficacy. Success, however, has been compromised. We are now faced with a long list of microbes that have found ways to circumvent different structural classes of drugs and are no longer susceptible to most, if not all, therapeutic regimens.
The means that microbes use to evade antibiotics certainly predate and outnumber the therapeutic interventions themselves. In a recent collection of soil-dwelling Streptomyces (the producers of many clinical therapeutic agents), every organism was multidrug resistant. Most were resistant to at least seven different antibiotics, and the phenotype of some included resistance to 15Ã¢â‚¬â€œ21 different drugs (D’Costa et al., 2006). Moreover, many isolates were resistant to daptomycin, quinupristin-dalfopristin, and telithromycinÃ¢â‚¬â€all drugs approved by the United States Food and Drug Administration (FDA) within the last decadeÃ¢â‚¬â€as well as purely synthetic agents such as ciprofloxacin. These data not only suggest that our surroundings can act as a reservoir for new (and old) resistance mechanisms, but that the drugs we use to treat infectious diseases have long-lasting effects outside of the hospital. Many antimicrobial molecules exist for millennia stably within the environment (Cook et al., 1989), where they select and promote growth of resistant strains.
Resistance to single antibiotics became prominent in organisms that encountered the first commercially produced antibiotics. The most notable example is resistance to penicillin among staphylococci, specified by an enzyme (penicillinase) that degraded the antibiotic (Barber, 1947). Over the years, continued selective pressure by different drugs has resulted in organisms bearing additional kinds of resistance mechanisms that led to multidrug resistance (MDR)Ã¢â‚¬â€novel penicillin-binding proteins (PBPs), enzymatic mechanisms of drug modification, mutated drug targets, enhanced efflux pump expression, and altered membrane permeability. Some of the most problematic MDR organisms that are encountered currently include Pseudomonas aeruginosa (another microbe of soil origin), Acinetobacter baumannii, Escherichia coli and Klebsiella pneumoniae bearing extended-spectrum ÃƒÂ¢-lactamases (ESBL), vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant MRSA, and extensively drug-resistant (XDR) Mycobacterium tuberculosis (Table 1). Some like methicillin-resistant S. aureus couple MDR with exceptional virulence capabilities (Miller et al., 2005). Others, including some strains of P. aeruginosa, A. baumannii, and K. pneumoniae, manage to evade every drug within the physician’s arsenal (Levin et al., 1999).
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