Multidrug-resistant<i>Mycobacterium tuberculosis</i>, Bangui, Central African Republic

Nouvel, Laurent-Xavier; Kassa-Kelembho, Eric; Vultos, Tiago Dos; Zandanga, Germain; Rauzier, Jean; Lafoz, Carmen; Martı́n, Carlos; Blázquez, Jesús; Talarmin, Antoine; Gicquel, Brigitte

doi:10.3201/eid1209.060361

Cited by 17 publications

(13 citation statements)

References 16 publications

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“…It has been discovered that many of these drug-resistant strains carry mutations in DNA repair genes, resulting in their mutator phenotype. ada/alkA, ogt [94,101] and ung [101] mutations have been discovered in Haarlem lineages, whereas mutT4, mutT2 and ogt have been discovered in W-Beijing lineages [100,102]. The same mutations are also observed in non-MDR strains, but this does not negate the point that their mutator phenotype may increase the possibility of them acquiring mutations against anti-tubercular drugs.…”

Section: Mycobacteria Chemotherapy and Evolutionmentioning

confidence: 92%

“…Finally, mutations to DNA damage repair proteins can lead to an increase in the mutation rate, as has been observed upon deletion of ung, uvrB, uvrD, fpg and udgB in Ms and ada/alkA together with ogt in MTB (Table 4 and Supplementary Table S3 at http://www.clinsci.org/cs/119/cs1190187add.htm). Furthermore, mutY [93] and mutT1 [94] mutations have been observed in drug-resistant phenotypes. Analysis of isoniazid-resistant strains has suggested that the SNPs responsible for resistance had arisen independently [82].…”

Section: Mycobacteria Chemotherapy and Evolutionmentioning

confidence: 99%

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DNA repair systems and the pathogenesis of Mycobacterium tuberculosis: varying activities at different stages of infection

2010

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Mycobacteria, including most of all MTB (Mycobacterium tuberculosis), cause pathogenic infections in humans and, during the infectious process, are exposed to a range of environmental insults, including the host's immune response. From the moment MTB is exhaled by infected individuals, through an active and latent phase in the body of the new host, until the time they reach the reactivation stage, MTB is exposed to many types of DNA-damaging agents. Like all cellular organisms, MTB has efficient DNA repair systems, and these are believed to play essential roles in mycobacterial pathogenesis. As different stages of infection have great variation in the conditions in which mycobacteria reside, it is possible that different repair systems are essential for progression to specific phases of infection. MTB possesses homologues of DNA repair systems that are found widely in other species of bacteria, such as nucleotide excision repair, base excision repair and repair by homologous recombination. MTB also possesses a system for non-homologous end-joining of DNA breaks, which appears to be widespread in prokaryotes, although its presence is sporadic within different species within a genus. However, MTB does not possess homologues of the typical mismatch repair system that is found in most bacteria. Recent studies have demonstrated that DNA repair genes are expressed differentially at each stage of infection. In the present review, we focus on different DNA repair systems from mycobacteria and identify questions that remain in our understanding of how these systems have an impact upon the infection processes of these important pathogens.

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Section: Mycobacteria Chemotherapy and Evolutionmentioning

confidence: 92%

Section: Mycobacteria Chemotherapy and Evolutionmentioning

confidence: 99%

DNA repair systems and the pathogenesis of Mycobacterium tuberculosis: varying activities at different stages of infection

2010

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“…Ninety percent of tuberculosis cases occur in developing countries due to inadequacies in the healthcare resources and patient follow-up [5]. The problem became global with the emergence of multidrug resistant strains of Mtb (MDR-TB), which currently are reported in all countries with the burden of disease not witnessed since before the advent of antibiotics [6,7].…”

Section: Introductionmentioning

confidence: 99%

Constraints of Drug Resistance in Mycobacterium tuberculosis - Prospects for Pharmacological Reversion of Susceptibility to Antibiotics

Ilin¹,

Kulmanov²,

Korotetskiy³

et al. 2017

TOPROCJ

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Emergence of multidrug resistant strains of Mycobacterium tuberculosis (MDR-TB) threatens humanity. This problem was complicated by the crisis in development of new anti-tuberculosis antibiotics. Induced reversion of drug resistance seems promising to overcome the problem. Successful clinical trial of a new anti-tuberculosis nanomolecular complex FS-1 has demonstrated prospectively of this approach in combating MDR-TB. Several clinical MDR-TB cultures were isolated from sputum samples prior and in the process of the clinical trial. Every isolate was tested for susceptibility to antibiotics and then they were sequenced for comparative genomics. It was found that the treatment with FS-1 caused an increase in the number of antibiotic susceptible strains among Mtb isolates that was associated with a general increase of genetic heterogeneity of the isolates. Observed impairing of phthiocerol dimycocerosate biosynthesis by disruptive mutations in ppsACD subunits indicated a possible virulence remission for the sake of persistence. It was hypothesized that the FS-1 treatment eradicated the most drug resistant Mtb variants from the population by aggravating the fitness cost of drug resistance mutations. Analysis of distribution of these mutations in the global Mtb population revealed that many of them were incompatible with each other and dependent on allelic states of many other polymorphic loci. The latter discovery may explain the negative correlation between the genetic heterogeneity of the population and the level of drug tolerance. To the best of our knowledge, this work was the first experimental confirmation of the drug induced antibiotic resistance reversion by the induced synergy mechanism that previously was predicted theoretically.

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“…While studying the genetic diversity of M. tuberculosis isolates in the Central African Republic (CAR), we described an MDR-prone family characterized by a T family spoligotype and a synonymous variation in the DNA repair gene mutT 1 [8]. This prompted us to screen our set of well-defined isolates from CAR [8,9] by sequencing putative anti-mutator genes including ada/alkA to identify other variations that could be markers of relevant clinical strains.…”

Section: Introductionmentioning

confidence: 99%

“…This prompted us to screen our set of well-defined isolates from CAR [8,9] by sequencing putative anti-mutator genes including ada/alkA to identify other variations that could be markers of relevant clinical strains.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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Background: Previous studies have suggested that variations in DNA repair genes of W-Beijing strains may have led to transient mutator phenotypes which in turn may have contributed to host adaptation of this strain family. Single nucleotide polymorphism (SNP) in the DNA repair gene mutT1 was identified in MDR-prone strains from the Central African Republic. A Mycobacteriumtuberculosis H37Rv mutant inactivated in two DNA repair genes, namely ada/alkA and ogt, was shown to display a hypermutator phenotype. We then looked for polymorphisms in these genes in Central African Republic strains (CAR).

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Multidrug-resistantMycobacterium tuberculosis, Bangui, Central African Republic

Cited by 17 publications

References 16 publications

DNA repair systems and the pathogenesis of Mycobacterium tuberculosis: varying activities at different stages of infection

DNA repair systems and the pathogenesis of Mycobacterium tuberculosis: varying activities at different stages of infection

Constraints of Drug Resistance in Mycobacterium tuberculosis - Prospects for Pharmacological Reversion of Susceptibility to Antibiotics

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

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