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Targeting Multidrug Resistant Mycobacterium tuberculosis HtrA2 with Identical Chemical Entities of Fluoroquinolones.

ABSTRACT: Tuberculosis is a highly communicable and chronic respiratory disease caused by pathogenic bacterium Mycobacterium tuberculosis. The drug - resistant species of Mycobacterium tuberculosis are tough to cure due to its resistant activity toward potential drugs. Available inhibitors of tuberculosis include few antimicrobial fluoroquinolone agents like ciprofloxacin, ofloxacin, and moxifloxacin to treat resistant Mycobacterium strains. Literature study elucidates that macromolecular target namely, HtrA2 of Mycobacterium tuberculosis play a dual role of protease and chaperone. These two activities are dependent on temperature, with low temperatures promoting the chaperone function and high temperatures promoting serine protease activity. Under normal physiological conditions HtrA2 acts as a quality control factor and promotes cell survival. In the present investigation, we screened fluoroquinolone such as ciprofloxacin, moxifloxacin and ofloxacin and their analogues based on better Docking score, absorption, distribution, metabolism and excretion screening and Lipinski's rule of 5, to find out their efficiency on resistant strain through in silico study. From the results observed, the analogues are suggested to be potent inhibitors of HtrA2 with sufficient scope for further exploration.

SUBMITTER: Daisy P

PROVIDER: S-EPMC3574531 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Targeting Multidrug Resistant Mycobacterium tuberculosis HtrA2 with Identical Chemical Entities of Fluoroquinolones.

Daisy P P Vijayalakshmi P P Selvaraj C C Singh S K SK Saipriya K K

Indian journal of pharmaceutical sciences 20120501 3

Tuberculosis is a highly communicable and chronic respiratory disease caused by pathogenic bacterium Mycobacterium tuberculosis. The drug - resistant species of Mycobacterium tuberculosis are tough to cure due to its resistant activity toward potential drugs. Available inhibitors of tuberculosis include few antimicrobial fluoroquinolone agents like ciprofloxacin, ofloxacin, and moxifloxacin to treat resistant Mycobacterium strains. Literature study elucidates that macromolecular target namely, H ...[more]

PMID: 23440996

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Project description:BackgroundMycobacterium tuberculosis complex (MTBC), the causative agent of tuberculosis (TB), is characterized by low sequence diversity making this bacterium one of the classical examples of a genetically monomorphic pathogen. Because of this limited DNA sequence variation, routine genotyping of clinical MTBC isolates for epidemiological purposes relies on highly discriminatory DNA fingerprinting methods based on mobile and repetitive genetic elements. According to the standard view, isolates exhibiting the same fingerprinting pattern are considered direct progeny of the same bacterial clone, and most likely reflect ongoing transmission or disease relapse within individual patients.Methodology/principal findingsHere we further investigated this assumption and used massively parallel whole-genome sequencing to compare one drug-susceptible (K-1) and one multidrug resistant (MDR) isolate (K-2) of a rapidly spreading M. tuberculosis Beijing genotype clone from a high incidence region (Karakalpakstan, Uzbekistan). Both isolates shared the same IS6110 RFLP pattern and the same allele at 23 out of 24 MIRU-VNTR loci. We generated 23.9 million (K-1) and 33.0 million (K-2) paired 50 bp purity filtered reads corresponding to a mean coverage of 483.5 fold and 656.1 fold respectively. Compared with the laboratory strain H37Rv both Beijing isolates shared 1,209 SNPs. The two Beijing isolates differed by 130 SNPs and one large deletion. The susceptible isolate had 55 specific SNPs, while the MDR variant had 75 specific SNPs, including the five known resistance-conferring mutations.ConclusionsOur results suggest that M. tuberculosis isolates exhibiting identical DNA fingerprinting patterns can harbour substantial genomic diversity. Because this heterogeneity is not captured by traditional genotyping of MTBC, some aspects of the transmission dynamics of tuberculosis could be missed or misinterpreted. Furthermore, a valid differentiation between disease relapse and exogenous reinfection might be impossible using standard genotyping tools if the overall diversity of circulating clones is limited. These findings have important implications for clinical trials of new anti-tuberculosis drugs.

Dataset Information

Targeting Multidrug Resistant Mycobacterium tuberculosis HtrA2 with Identical Chemical Entities of Fluoroquinolones.

Publications

Targeting Multidrug Resistant Mycobacterium tuberculosis HtrA2 with Identical Chemical Entities of Fluoroquinolones.

Similar Datasets

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