Bacterial hypermutation: clinical implications

Abstract

Heritable hypermutation in bacteria is mainly due to alterations in the methyl-directed mismatch repair (MMR) system. MMR-deficient strains have been described from several bacterial species, and all of the strains exhibit increased mutation frequency and recombination, which are important mechanisms for acquired drug resistance in bacteria. Antibiotics select for drug-resistant strains and refine resistance determinants on plasmids, thus stimulating DNA recombination via the MMR system. Antibiotics can also act as indirect promoters of antibiotic resistance by inducing the SOS system and certain error-prone DNA polymerases. These alterations have clinical consequences in that efficacious treatment of bacterial infections requires high doses of antibiotics and/or a combination of different classes of antimicrobial agents. There are currently few new drugs with low endogenous resistance potential, and the development of such drugs merits further research. IntroductionEradication of infectious diseases is constantly challenged by micro-organisms that develop new survival strategies. Previous studies suggest that mutational events play a predominant role in bacterial adaptation and confer a selective advantage (Chou et al., 2009;Cooper, 2007). Early experiments aimed at detecting mutators used mutagenized laboratory strains of bacteria, sometimes coupled with different selection strategies. LeClerc et al. (1996) reported high mutation frequency among Escherichia coli and Salmonella pathogens, challenging the theory that mutators were rare among bacterial populations. Taken together, these findings demonstrated that natural populations could respond to environmental selection in two ways, i.e. by enhanced mutation frequencies and by recombination. Transient mutator status, which involves reversion or recombination within the mutator alleles or depletion of the methyl-directed mismatch repair (MMR) system proteins, allows the organism to temporarily benefit from the elevated mutation frequency for adaptation while reducing the risk of accumulating deleterious mutations. Using a mathematical model, Rosche & Foster (1999) showed that transient hypermutators play a role in adaptive mutation in E. coli. Molecular mechanisms of hypermutationProteins involved in the DNA mismatch repair pathway help replace nucleotides introduced erroneously into the replicated DNA and also hinder recombination between non-identical DNA sequences. Deficiencies in any of the DNA mismatch repair pathway mechanisms can lead to a hypermutator phenotype. DNA repairSiegel & Bryson (1967) discovered the mutS gene in an azaserine-resistant derivative of E. coli that had a mutator phenotype and carried a deletion in the mutS gene. The majority of naturally occurring strong mutators have defects in the MMR system; the mutations are mainly in mutS (Oliver et al., 2002), but deletions in genes encoding beta-clamp proteins and in mutH, mutL and mutU (uvrD) have also been described (Fig. 1). Inactivation of basal excision repair genes, e.g. mutY, mutM, ...

Adaptive tuning of mutation rates allows fast response to lethal stress in Escherichia coli

“…Bacteria undergoing antibiotic treatment or cancer cells exposed to chemotherapy are prime examples of cells exposed to stressful conditions. Therefore, hypermutation should be considered a risk for both the development of multidrug resistance in pathogenic bacteria (Hammerstrom et al, 2015; Jolivet-Gougeon et al, 2011; Blázquez, 2003; Chopra et al, 2003) and cancer relapses as recently shown (Wang et al, 2016). Targeting hypermutation could pave the way not only for the development of novel anti-cancer therapies, but also for containing the spread of multidrug tolerant pathogens and even for the generation of robust, stress-resistant strains for use in various industrial processes.…”

Measurably evolving pathogens in the genomic era

“…Molecular evolution can also vary temporally, as was recently reported for Yersinia pestis and hypothesized to reflect strong demographic fluctuations [39]. On a shorter time scale, modulation of DNA repair pathways can increase the substitution rate dramatically in a process called hypermutation, which has been shown to be adaptively important, for example to gain antibiotic resistance [40,41]. The life cycles of many infectious bacterial pathogens introduce further possible causes of temporal variation in evolutionary rates.…”

Lytic phages obscure the cost of antibiotic resistance in Escherichia coli

“…This is potentially relevant outside the laboratory given that mutator bacteria are common in clinical settings, particularly in chronic infections (Oliver et al, 2000;Denamur et al, 2002), and are frequently associated with antibiotic resistance Baquero et al, 2005;Maciá et al, 2005). Crucially, the mutator phenotype of clinical isolates, including E. coli, is frequently because of mutations in mismatch repair genes including mutS (LeClerc et al, 1996;Chopra et al, 2003;Li et al, 2003;Jolivet-Gougeon et al, 2011), the same mechanism as in our experiments. Mutator No phage HK578 T4 Figure 6 Selective effect of an elevated mutation rate.…”