Hypermutation as a Factor Contributing to the Acquisition of Antimicrobial Resistance

Clinical Infectious Diseases, Nov 2003

Contrary to what was thought previously, bacteria seem to be, not merely spectators to their own evolution, but, through a variety of mechanisms, able to increase the rate at which mutations occur and, consequently, to increase their chances of becoming resistant to antibiotics. Laboratory studies and mathematical models suggest that, under stressful conditions, such as antibiotic challenge, selective pressure favors mutator strains of bacteria over nonmutator strains. These hypermutable strains have been found in natural bacterial populations at higher frequencies than expected. The presence of mutator strains in the clinical setting may indicate an enhanced risk of acquiring antibiotic resistance through mutational and recombinational events. In addition, some antibiotics are inducers of mechanisms that transiently increase the mutation rate, and thus probably act, not only as mere selectors of antibiotic resistant clones, but also as resistance-promoters.

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Hypermutation as a Factor Contributing to the Acquisition of Antimicrobial Resistance

ANTIMICROBIAL RESISTANCE • CID Hypermutation as a Factor Contributing to the Acquisition of Antimicrobial Resistance Jes u´s Bla´ zquez () 0 1 0 Received 13 May 2003; accepted 5 July 2003; electronically published 30 September 2003. Financial support: This work was supported in part by the Ministerio de Sanidad y Consumo (Fondo de Investigacio ́n Sanitaria) (grant 01/0020-02) and the Ministerio de Ciencia y Tecnolog ́ıa (grant BMC2001-0012), Spain. Centro Nacional de Biotecnologia, CSIC, Campus Universidad Autonoma de Madrid , Cantoblanco, 28049 Madrid , Spain 1 Departamento de Biotecnologia Microbiana, Centro Nacional de Biotecnologia, Consejo Superior de Investigaciones Cientificas, Campus Universidad Autonoma de Madrid , Spain Contrary to what was thought previously, bacteria seem to be, not merely spectators to their own evolution, but, through a variety of mechanisms, able to increase the rate at which mutations occur and, consequently, to increase their chances of becoming resistant to antibiotics. Laboratory studies and mathematical models suggest that, under stressful conditions, such as antibiotic challenge, selective pressure favors mutator strains of bacteria over nonmutator strains. These hypermutable strains have been found in natural bacterial populations at higher frequencies than expected. The presence of mutator strains in the clinical setting may indicate an enhanced risk of acquiring antibiotic resistance through mutational and recombinational events. In addition, some antibiotics are inducers of mechanisms that transiently increase the mutation rate, and thus probably act, not only as mere selectors of antibiotic resistant clones, but also as resistance-promoters. - Societies—at least the developed ones—are facing the problem of an increasing number of antibiotic-resistant microbial pathogens. Paradoxically, this is a consequence of the success of antibiotic therapy. This success led to the belief that any infectious disease could be treated, and even eliminated, with these “miraculous” drugs. Nevertheless, during the past 6 decades, we have been witness to one of the most rapid and striking phenomena of biological evolution, which has been provoked, unfortunately, by humankind: the adaptation of bacteria to antibiotics. The extended use—and, all too often, abuse and misuse—of these molecules has produced an impressive effect, leading to the selection and spread of resistant bacteria. Bacteria may acquire antibiotic resistance in 2 main ways: through horizontal transfer (i.e., acquisition of already-made and pretested resistance genes from other microorganisms) and through mutation in different chromosomal loci. Only the latter will be considered here. Although it has been stated that, because of the low frequency at which mutations occur, resistance in natural environments is mainly acquired through horizontal transfer [1], a number of mechanisms of antibiotic resistance are based on mutational events [2]. The sequence of a gene encoding the target of an antibacterial molecule may be altered by mutation, leading to the inability of that molecule to inhibit its activity. For instance, most of the known mechanisms of bacterial resistance to some antibiotics, such as rifamicins and fluoroquinolones, are caused by mutations in the genes encoding the targets of these molecules (RpoB and DNA-topoisomerases, respectively). Variation in the expression of antibiotic uptake or of efflux systems may also be modified by mutation, leading to an increased resistance to antibiotics. For instance, the reduced expression or absence of the OprD porin of Pseudomonas aeruginosa reduces the permeability of the cell wall to carbapenems [3]. Most of the antibiotic resistance phenotypes associated with uptake and with efflux systems are caused by mutations in regulatory genes or their promoter regions [4]. An additional problem caused by those mutations that lead to increased expression of efflux systems is that, in general, such mutations confer resistance to multiple antibiotics. For example, mutations in the Escherichia coli mar gene affect the expression of about 60 different genes, including down-regulation of OmpF and up-regulation of AcrAB. AcrAB is involved in the efflux of b-lactams, fluoroquinolones, chloramphenicol, and tetracycline [5]. In P. aeruginosa, mutation in mexR up-regulates the mexA-mexB-oprM operon and raises the MICs of most b-lactams, fluoroquinolones, tetracyclines, chloramphenicol, and macrolides [4]. Finally, overproduction of antibiotic-inactivating enzymes may be achieved through mutational events. Many gram-negative microorganisms produce chromosomal b-lactamases (such as AmpC) at low levels. Mutations producing up-regulation of their expression, and, consequently, constitutive hyperproduction of AmpC, lead to resistance to most cephalosporins [6]. In addition, there are some clinically relevant pathogens for which plasmid- or transposon-mediated mechanisms of resistance ha (...truncated)


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George M. Eliopoulos, Jesús Blázquez. Hypermutation as a Factor Contributing to the Acquisition of Antimicrobial Resistance, Clinical Infectious Diseases, 2003, pp. 1201-1209, 37/9, DOI: 10.1086/378810