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Mycobacterium tuberculosis AND drug use and [keywords]
- Impact of isoniazid resistance on virulence of global and south Indian clinical isolates of Mycobacterium tuberculosis. [REVIEW]
- Tuberculosis (Edinb) 2014 Sep 6.
Isoniazid (INH) is the only anti-tuberculous drug for which a relationship has been noticed between acquisition of resistance and lack of virulence. Mutation in katG gene is the chief cause for INH resistance in Mycobacterium tuberculosis (MTB). Classical studies have demonstrated that INH-resistant (INH(r)) mutants with a defective katG gene were catalase deficient and markedly attenuated in guinea pigs. Also, earlier studies on south Indian INH(r) isolates were shown to have lower virulence and higher susceptibility to H2O2. However, later studies including that of our's suggest that INH resistance is not always accompanied by compromised virulence and/or survival. Therefore, this review focuses on the influence of INH resistance on virulence of MTB from global and south Indian isolates.
- Mycobacterial interspersed repetitive unit typing and mutational profile for multidrug-resistant and extensively drug-resistant tuberculosis surveillance in Portugal: a 3-year period overview. [JOURNAL ARTICLE]
- Int J Antimicrob Agents 2014 Sep 6.
Multidrug tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) cases constitute a serious health problem in Portugal, of which the majority of isolates belong to the Lisboa family and the Q1 cluster, highly related to the Lisboa family. Here we sought to investigate the molecular basis of resistant TB as well as to determine the prevalence of specific drug resistance mutations and their association with MDR-TB and/or XDR-TB. In total, 74 Mycobacterium tuberculosis clinical isolates collected in Lisbon Health Region were genotyped by 24-loci mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU-VNTR), and the mutational profile associated with first- and second-line drug resistance was studied. Seven new mutations were found, whilst the remaining 28 mutations had been previously associated with drug resistance. None of the mutations was specifically associated with MDR-TB. The mutational patterns observed among isolates belonging to Lisboa3 and Q1 clusters were also observed in isolates with unique MIRU-VNTR patterns but closely related to these strains. Such data suggest that the genotyping technique employed discriminates isolates with the same mutational profile. To establish the most adequate genotyping technique, the discriminatory power of three different MIRU-VNTR sets was analysed. The 15-loci MIRU-VNTR set showed adequate discriminatory power, comparable with the 24-loci set, allowing clustering of 60% and 86% of the MDR-TB and XDR-TB isolates, respectively, the majority of which belonged to the Lisboa3 and Q1 clusters. From an epidemiological standpoint, this study suggests combined mutational and genotyping analysis as a valuable tool for drug resistance surveillance.
- Discovery of a capuramycin analog that kills nonreplicating Mycobacterium tuberculosis and its synergistic effects with translocase I inhibitors. [JOURNAL ARTICLE]
- J Antibiot (Tokyo) 2014 Oct 1.
Capuramycin (1) and its analogs are strong translocase I (MurX/MraY) inhibitors. In our structure-activity relationship studies of capuramycin analogs against Mycobacterium tuberculosis (Mtb), we observed for the first time that a capuramycin analog, UT-01320 (3) killed nonreplicating (dormant) Mtb at low concentrations under low oxygen conditions, whereas selective MurX inhibitors killed only replicating Mtb under aerobic conditions. Interestingly, 3 did not exhibit MurX enzyme inhibitory activity even at high concentrations, however, 3 inhibited bacterial RNA polymerases with the IC50 values of 100-150 nM range. A new RNA polymerase inhibitor 3 displayed strong synergistic effects with a MurX inhibitor SQ 641 (2), a promising preclinical tuberculosis drug.The Journal of Antibiotics advance online publication, 1 October 2014; doi:10.1038/ja.2014.133.
- Endothelin system has a significant role in the pathogenesis and progression of Mycobacterium tuberculosis infection. [JOURNAL ARTICLE]
- Infect Immun 2014 Sep 29.
Tuberculosis (TB) remains a major global health problem and although multiple studies have addressed the relationship between Mycobacterium tuberculosis (Mtb) and the host on an immunological level, few studies have addressed the impact of host physiological responses. Proteases produced by bacteria have been associated with important alterations in the host tissues and a limited number of these enzymes have been characterized in mycobacterial species. Mtb produces a protease called Zmp1, which appears to be associated with virulence, which has a putative action as an endothelin converting enzyme. Endothelins are a family of vasoactive peptides, of which 3 distinct isoforms exist and ET-1 is the most abundant and the best characterized isoform. The aim of this work was to characterize the Zmp1 protease and evaluate its role in pathogenicity. Here we have shown that M. tuberculosis produces and secretes an enzyme with ET-1 cleavage activity. These data demonstrate a possible role of Zmp1 for mycobacteria host interactions, and highlights its potential as a drug target. Moreover, the results suggest that endothelin pathways have a role in pathogenesis of Mtb infections, and ETA or ETB receptor signaling can modulate the host response to the infection. We hypothesize that a balance between Zmp1 control of ET-1 levels and ETA/ETB signaling can allow Mtb adaptation and survival in the lung tissues.
- Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery. [JOURNAL ARTICLE]
- Proc Natl Acad Sci U S A 2014 Sep 29.
Caseinolytic peptidase P (ClpP), a double-ring peptidase with 14 subunits, collaborates with ATPases associated with diverse activities (AAA+) partners to execute ATP-dependent protein degradation. Although many ClpP enzymes self-assemble into catalytically active homo-tetradecamers able to cleave small peptides, the Mycobacterium tuberculosis enzyme consists of discrete ClpP1 and ClpP2 heptamers that require a AAA+ partner and protein-substrate delivery or a peptide agonist to stabilize assembly of the active tetradecamer. Here, we show that cyclic acyldepsipeptides (ADEPs) and agonist peptides synergistically activate ClpP1P2 by mimicking AAA+ partners and substrates, respectively, and determine the structure of the activated complex. Our studies establish the basis of heteromeric ClpP1P2 assembly and function, reveal tight coupling between the conformations of each ring, show that ADEPs bind only to one ring but appear to open the axial pores of both rings, provide a foundation for rational drug development, and suggest strategies for studying the roles of individual ClpP1 and ClpP2 rings in Clp-family proteolysis.
- Evaluation of the microscopic observation drug susceptibility assay for the rapid detection of MDR-TB and XDR-TB in China: a prospective multicentre study. [JOURNAL ARTICLE]
- J Antimicrob Chemother 2014 Sep 28.
To perform a multicentre study evaluating the performance of the microscopic observation drug susceptibility (MODS) assay for the detection of MDR-TB and XDR-TB in high-burden resource-limited settings.We performed a prospective diagnostic accuracy study of drug-resistant TB suspects from outpatient and inpatient settings in five laboratories in China. Sputum was tested by smear microscopy, liquid [mycobacterial growth indicator tube (MGIT)] culture and the MODS assay at each site. Drug susceptibility testing (DST) was by MODS and an indirect 1% proportion method. The reference standard for Mycobacterium tuberculosis detection was growth on MGIT culture; the 1% proportion method was the reference standard for rifampicin, isoniazid, ofloxacin, kanamycin and capreomycin DST.M. tuberculosis was identified by reference standard culture among 213/532 (40.0%) drug-resistant TB suspects. Overall MODS sensitivity for M. tuberculosis detection was 87.8%-94.3% and specificity was 96.8%-100%. For drug-resistant TB diagnosis, excellent agreement was obtained for all drugs tested at the majority of sites. The accuracy was 87.1%-96.7% for rifampicin, 87.1%-93.3% for isoniazid, 92.7%-100% for ofloxacin, 90.9%-100% for kanamycin and 90.2%-100% for capreomycin. The median time to culture positivity was significantly shorter for MODS than for the MGIT liquid culture (8 days versus 11 days, P < 0.001). The contamination rate ranged between 2.1% and 5.3%.In the study settings, MODS provided high sensitivity and specificity for rapid diagnosis of TB and drug-resistant TB. We consider it to have a strong potential for timely detection of MDR-TB and XDR-TB in high-burden resource-limited settings.
- Antimycobacterial activity of selected medicinal plants traditionally used in Sudan to treat infectious diseases. [JOURNAL ARTICLE]
- J Ethnopharmacol 2014 Sep 24.
The emergence of multidrug-resistant strains of Mycobacterium tuberculosis underscores the need for continuous development of new and efficient methods to determine the susceptibility of isolates of M. tuberculosis in the search for novel antimycobacterial agents. Natural products constitute an important source of new drugs, and design and implementation of antimycobacterial susceptibility testing methods are necessary to evaluate the different extracts and compounds. In this study we have explored the antimycobacterial properties of 50 ethanolic extracts from different parts of 46 selected medicinal plants traditionally used in Sudan to treat infectious diseases.Plants were harvested and ethanolic extracts were prepared. For selected extracts, fractionation with hydrophilic and hydrophobic solvents was undertaken. A luminometry-based assay was used for determination of mycobacterial growth in broth cultures and inside primary human macrophages in the presence or absence of plant extracts and fractions of extracts. Cytotoxicity was also assessed for active fractions of plant extracts.Of the tested extracts, three exhibited a significant inhibitory effect on an avirulent strain of M. tubercluosis (H37Ra) at the initial screening doses (125 and 6.25µg/ml). These were bark and leaf extracts of Khaya senegalensis and the leaf extract of Rosmarinus officinalis L. Further fractions of these plant extracts were prepared with n-hexane, chloroform, ethyl acetate, n-butanol, ethanol and water, and the activity of these extracts was retained in hydrophobic fractions. Cytotoxicity assays revealed that the chloroform fraction of K. senegalensis bark was non-toxic to human monocyte-derived macrophages and other cell types at the concentrations used and hence, further analysis, including assessment of IC50 and intracellular activity was done with this fraction.These results encourage further investigations to identify the active compound(s) within the chloroform fraction of K. senegalensis bark.
- Structural basis for inhibition of mycobacterial and human adenosine kinase by 7-substituted 7-(het)aryl-7-deazaadenine ribonucleosides. [JOURNAL ARTICLE]
- J Med Chem 2014 Sep 26.
Adenosine kinase (ADK) from Mycobacterium tuberculosis (Mtb) was selected as a target for design of antimycobacterial nucleosides. Screening of 7-(het)aryl-7-deazaadenine ribonucleosides with Mtb and human (h) ADKs and testing with wild-type and drug-resistant Mtb strains identified specific inhibitors of Mtb ADK with micromolar antimycobacterial activity and low cytotoxicity. X-ray structures of complexes of Mtb and hADKs with 7-ethynyl-7-deazaadenosine showed differences in inhibitor interactions in the adenosine binding sites. 1D 1H STD NMR experiments revealed that these inhibitors are readily accommodated into the ATP and adenosine binding sites of Mtb ADK, whereas they bind preferentially into the adenosine site of hADK. Occupation of the Mtb ADK ATP site with inhibitors and formation of catalytically less competent semi-open conformation of MtbADK after inhibitor binding in the adenosine site explain the lack of phosphorylation of 7-substituted-7-deazaadenosines. Semiempirical quantum mechanical analysis confirmed different affinity of nucleosides for the Mtb ADK adenosine and ATP sites.
- Gene mutations in Mycobacterium tuberculosis: Multidrug-resistant TB as an emerging global public health crisis. [REVIEW]
- Tuberculosis (Edinb) 2014 Aug 30.
Against a constant background of established infections, epidemics of new and old infectious diseases periodically emerge, greatly magnifying the global burden of infections. TB poses formidable challenges to the global health at the public health and scientific level by acquiring gene mutation into anti TB drugs specially rifampin and isoniazid which leads resistant to drug regime and treatment forms. Our tools to combat MDR (multidrug resistant) TB are dangerously out of date and ineffective. Besides new tools (TB drugs, vaccines, diagnostics), we also need new strategies to identify key Mycobacterium tuberculosis and human host interaction. It is all equally important that we build up high quality clinical trial capacity and bio banks for TB biomarkers identification. But most important is global commitment at all levels to roll back TB before it expose us again. Rapid development of drug resistance caused by M. tuberculosis has lead to measure resistance accurately and easily. This knowledge will certainly help us to understand how to prevent the occurrence of drug resistance as well as identifying genes associated with new drug resistance.
- Expression Profile of Markers of Apoptosis, Injury and Oxidative Stress in Human Lung Epithelium Cells-A5449 Receiving Chronic Exposure of Potential Anti-Tubercular Drug-trans-Cyclohexane-1, 4-Diamine Derivative-"9u". [Journal Article]
- Toxicol Int 2014 May; 21(2):172-8.
Earlier, we had reported the synthesis of a library of symmetrical trans-cyclohexane-1,4-diamine derivatives and evaluated them for their anti-mycobacterium activity in the H37RV strain of Mycobacterium tuberculosis. A range of efficacy was recorded in different derivatives and the compound "9u" having an i-propyl group substitution at the p-position was found to be the most effective. The compound "9u" was found to be safe for cytotoxic and genotoxic responses in human lung epithelium cells-A549, even up to many fold higher than that required to kill M. tuberculosis. Hence, compound "9u" was inferred to be a potential anti-tuberculosis drug of choice. However, the biological safety of compound "9u" upon chronic exposure was still to be answered because anti-tuberculosis (TB) treatment requires a minimum of 6 months' exposure of host systems and most of the available anti-TB drugs are known to induce apoptosis, oxidative stress and injury during such exposures. Thus, the present investigations were aimed to study the alterations, if any, in the expression profile (mRNA and protein) of markers associated with apoptosis, injury and oxidative stress in human lung epithelium cells-A549 receiving a chronic exposure of the potential anti-TB compound "9u." Our findings demonstrate that there was a statistically insignificant transient shift (until 3 weeks) in the markers of apoptosis, injury and oxidative stress, after which expression changes were similar to baseline, when compared with unexposed cells of respective time periods. The studied markers showed linearity in the trend at both mRNA and protein level, indicating the suitability of the test system selected in the study. The data confirm the therapeutic potential of compound "9u" for even long-term treatment against M. tuberculosis without having any significant apoptosis, injury and oxidative stress.