Antimicrobial agent resistance in mycobacteria: molecular genetic insights

Musser, James M.

doi:10.1128/cmr.8.4.496

Cited by 508 publications

(137 citation statements)

References 165 publications

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“…In fact, 58.7% (27/46) of the phenotypically MDR isolates did not hybridize with rpoB531 wild type probe. Furthermore, the codon 531 is well known to be a hot spot in rpoB gene for mutational changes in Mtb (Musser, 1995). The mutations at rpoB526 codon occurred in 10.9% (5/46) phenotypically MDR strains.…”

Section: Resultsmentioning

confidence: 99%

Molecular analysis of multidrug resistantMycobacterium tuberculosis isolates from Morocco

Sabouni¹,

Kourout

Chaoui

et al. 2008

Ann. Microbiol.

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Tuberculosis remains a global threat to public health. Considerable efforts have been made to combat this disease. However, the emergence of Mycobacterium tuberculosis (Mtb) strains resistant to the major anti-tuberculosis drugs especially multidrug resistant (MDR) strains poses a deadly threat to control programs. The present study aims to identify the most common mutations within multidrug-resistant M. tuberculosis Moroccan isolates in order to use them as molecular markers for early and rapid detection of multidrug resistant strains. For that, all M. tuberculosis isolates received during 2002-2003 in the National Reference Laboratory of Tuberculosis in Morocco were subject to drug susceptibility tests for rifampicin and isoniazid and to a PCR probe method to detect specific mutation. Sequencing was performed for all genotypic rifampicin resistant isolates and also for four genotypic isoniazid resistant isolates randomly selected. Out of 187 M. tuberculosis positive cultures, 46 (24.6%) were phenotypically resistant to both rifampicin and isoniazid. Nucleotide mutations in rpoB531, rpoB526, rpoB516, katG315 and inh-15 codons associated with resistance to rifampin (RIF) and isoniazid (INH) were found respectively in 37/46 (80.4%) and 43/46 (93.5%) isolates. Genotypic multi drug resistance was then confirmed in 74% (34/46) isolates. The mutations at codon 315 of katG gene and at codons 531, 526 and 516 of rpoB gene are frequently found in MDR isolates which confirm their strong implication in the development of multidrug resistant tuberculosis. We concluded that these mutations are useful as molecular markers for detection of multidrug resistant isolates but are not yet sufficient to fully predict M. tuberculosis multidrug resistance.

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Section: Resultsmentioning

confidence: 99%

Molecular analysis of multidrug resistantMycobacterium tuberculosis isolates from Morocco

Sabouni¹,

Kourout

Chaoui

et al. 2008

Ann. Microbiol.

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“…For example, in E. coli, mutations in the gyrase and topoisomerase genes cause resistance to fluorquinolone antibiotics [29]. The resistance to rifampicin and streptomycin in mycobacteria and other microorganisms is mediated by point mutations in the RNA polymerase and ribosomal genes, respectively [30]. During the treatment of an infection with these antibiotics, resistant bacterial subclones emerge very rapidly.…”

Section: Point Mutations Deletions and Pathoadaptive Mutations Are Imentioning

confidence: 99%

Evolution of bacterial pathogenesis

Ziebuhr¹,

Ohlsen²,

Karch³

et al. 1999

Cellular and Molecular Life Sciences (CMLS)

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The evolution of bacteria is associated with continuous generation of novel genetic variants. The major driving forces in this process are point mutations, genetic rearrangements, and horizontal gene transfer. A large number of human and animal bacterial pathogens have evolved the capacity to produce virulence factors that are directly involved in infection and disease. Additionally, many bacteria express resistance traits against antibiotics. Both virulence factors and resistance determinants are subject to intrastrain genetic and phenotypic variation. They are often encoded on unstable DNA regions. Thus, they can be readily transferred to bacteria of the same species or even to non-related prokaryotes. This review article focuses on the main mechanisms of bacterial microevolution responsible for the rapid emergence of variants with novel virulence and resistance properties. In addition, processes of macroevolution are described with special emphasis on gene transfer and fixation of adaptive mutations in the genome of pathogens.

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“…We presume that this is one of the natural means by which resistance to a drug could be generated. Previous reports indicated that mutations in the quinolone resistance-determining region (QRDR) of the DNA gyrase A subunit are the primary cause of high levels of¯uoroquinolone resistance in mycobacteria (Musser 1995;Blanchard 1996). However, the CIP r clone, although it bears a mutation within the QRDR, exhibited reversal of drug resistance when it was grown in the presence of verapamil (Banerjee et al 1996).…”

Section: Discussionmentioning

confidence: 93%

Involvement of a natural transport system in the process of efflux-mediated drug resistance in Mycobacterium smegmatis

Banerjee

Bhatt²,

Misra³

et al. 2000

Mol Gen Genet

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The phosphate-specific transporter (Pst) in bacteria is a multi-subunit system which belongs to the ABC family of transporters. The gene forms part of an operon and it is involved in phosphate uptake in prokaryotes. Its import function is known to be operative only under conditions of phosphate starvation. However, we found overexpression of this transporter in a Mycobacterium smegmatis strain selected for ciprofloxacin resistance (CIPr) which was grown under conditions in which the phosphate-scavenging function of this operon was inoperative. In CIPr cells, active efflux of the drug plays a predominant role in conferring high levels of fluoroquinolone resistance. We therefore investigated the role of this transporter in the process of efflux-mediated drug resistance by inactivating the pst operon in the CIPr strain. Phenotypic characterization of the resulting strain, CIPrd, showed a striking reduction in the minimal inhibitory concentration (MIC) of ciprofloxacin and in the drug extrusion profile as well. Genotype analysis, on the other hand, revealed partial disruption of the pst operon in CIPrd as a consequence of transporter gene amplification. Furthermore, disruption of this operon in wild-type cells resulted in hypersensitivity to ciprofloxacin and other xenobiotics to which CIPr cells exhibited cross-resistance. Thus our results provide strong evidence that Pst is a natural membrane transport system that has the ability to promote drug efflux in addition to its phosphate-scavenging function in the CIPr strain.

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Antimicrobial agent resistance in mycobacteria: molecular genetic insights

Cited by 508 publications

References 165 publications

Molecular analysis of multidrug resistantMycobacterium tuberculosis isolates from Morocco

Molecular analysis of multidrug resistantMycobacterium tuberculosis isolates from Morocco

Evolution of bacterial pathogenesis

Involvement of a natural transport system in the process of efflux-mediated drug resistance in Mycobacterium smegmatis

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