A non-sense mutation in the putative anti-mutator gene ada/alkA of Mycobacterium tuberculosis and M. bovis isolates suggests convergent evolution

Nouvel, Laurent-Xavier; Vultos, Tiago Dos; Kassa-Kelembho, Eric; Rauzier, Jean; Gicquel, Brigitte

doi:10.1186/1471-2180-7-39

Cited by 13 publications

(7 citation statements)

References 23 publications

(24 reference statements)

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“…In the same study, the ada/alkA gene was found to be highly polymorphic in a large proportion of the clinical strains assessed. The ada/alkA variants have a 79 AMBER codon in the ada part of the operon, suggesting that induction of both alkA and ogt differ in these variants (Friedberg et al , 1995; Nouvel et al , 2006, 2007). Polymorphisms in clinical strains associated with epidemics, such as the Haarlem (Mardassi et al , 2005) and W‐Beijing (Rad et al , 2003) genotypes, have been described for the ogt gene.…”

Section: Variation and Conservation In M Tuberculosis Dna Repair Genesmentioning

confidence: 99%

DNA repair inMycobacterium tuberculosisrevisited

et al. 2009

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Our understanding of Mycobacterium tuberculosis DNA repair mechanisms is still poor compared with that of other bacterial organisms. However, the publication of the first complete M. tuberculosis genome sequence 10 years ago boosted the study of DNA repair systems in this organism. A first step in the elucidation of M. tuberculosis DNA repair mechanisms was taken by Mizrahi and Andersen, who identified homologs of genes involved in the reversal or repair of DNA damage in Escherichia coli and related organisms. Genes required for nucleotide excision repair, base excision repair, recombination, and SOS repair and mutagenesis were identified. Notably, no homologs of genes involved in mismatch repair were identified. Novel characteristics of the M. tuberculosis DNA repair machinery have been found over the last decade, such as nonhomologous end joining, the presence of Mpg, ERCC3 and Hlr - proteins previously presumed to be produced exclusively in mammalian cells - and the recently discovered bifunctional dCTP deaminase:dUTPase. The study of these systems is important to develop therapeutic agents that can counteract M. tuberculosis evolutionary changes and to prevent adaptive events resulting in antibiotic resistance. This review summarizes our current understanding of the M. tuberculosis DNA repair system.

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Section: Variation and Conservation In M Tuberculosis Dna Repair Genesmentioning

confidence: 99%

DNA repair inMycobacterium tuberculosisrevisited

et al. 2009

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“…Different mutations in this gene have been found in strains from the Euro-American lineage (spoligotype Haarlem) (2). Rv1317c (alkA) is part of the AdaA-AlkA adaptive response in M. tuberculosis, and multiple mutations have been found in strains from lineage 4 (Euro-American), lineage 2 (the same mutation has been found previously in the W-Beijing 210 strain, which belongs to the RD142 sublineage), and in Mycobacterium bovis (29). It has been suggested that a defective adaptive response by these genes will confer a selective advantage to M. tuberculosis (54).…”

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confidence: 99%

Beijing Sublineages of Mycobacterium tuberculosis Differ in Pathogenicity in the Guinea Pig

Kato‐Maeda

Shanley

Ackart

et al. 2012

Clin. Vaccine Immunol.

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ABSTRACTThe Beijing family ofMycobacterium tuberculosisstrains is part of lineage 2 (also known as the East Asian lineage). In clinical studies, we have observed that isolates from the sublineage RD207 of lineage 2 were more readily transmitted among humans. To investigate the basis for this difference, we tested representative strains with the characteristic Beijing spoligotype from four of the five sublineages of lineage 2 in the guinea pig model and subjected these strains to comparative whole-genome sequencing. The results of these studies showed that all of the clinical strains were capable of growing and causing lung pathology in guinea pigs after low-dose aerosol exposure. Differences between the abilities of the four sublineages to grow in the lungs of these animals were not overt, but members of RD207 were significantly more pathogenic, resulting in severe lung damage. The RD207 strains also induced much higher levels of markers associated with regulatory T cells and showed a significant loss of activated T cells in the lungs over the course of the infections. Whole-genome sequencing of the strains revealed mutations specific for RD207 which may explain this difference. Based on these data, we hypothesize that the sublineages ofM. tuberculosisare associated with distinct pathological and clinical phenotypes and that these differences influence the transmissibility of particularM. tuberculosisstrains in human populations.

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“…These include isolates with inactivation of the alkylation damage repair gene ada/alkA in several Mycobacterium tuberculosis isolates and in one Mycobacterium bovis strain (Nouvel et al, 2007) and E. coli isolates with an inactivated dnaQ gene, which encodes the epsilon subunit of DNA polymerase III (Itakura et al, 2008). Recently, Rodríguez-Rojas & Blázquez (2009) looked for additional genes involved in hypermutability by screening a Pseudomonas aeruginosa library with random insertions.…”

Section: Dna Repairmentioning

confidence: 99%

Bacterial hypermutation: clinical implications

Jolivet‐Gougeon

Kovács

Gall‐David

et al. 2011

Journal of Medical Microbiology

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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, ...

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A non-sense mutation in the putative anti-mutator gene ada/alkA of Mycobacterium tuberculosis and M. bovis isolates suggests convergent evolution

Cited by 13 publications

References 23 publications

DNA repair inMycobacterium tuberculosisrevisited

DNA repair inMycobacterium tuberculosisrevisited

Beijing Sublineages of Mycobacterium tuberculosis Differ in Pathogenicity in the Guinea Pig

Bacterial hypermutation: clinical implications

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