Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis

Gandhi, Neel R.; Nunn, Paul; Dheda, Keertan; Schaaf, H. Simon; Zignol, Matteo; Soolingen, Dick van; Jensen, Paul; Bayona, Jaime

doi:10.1016/s0140-6736(10)60410-2

Cited by 896 publications

(722 citation statements)

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“…The emergence of multidrugresistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis has challenged conventional anti-TB therapy and threatens global disease control of TB [2,3]. The development of new anti-TB drugs is urgently required [4].…”

Section: Dear Editormentioning

confidence: 99%

Crystal structure of L,D-transpeptidase LdtMt2 in complex with meropenem reveals the mechanism of carbapenem against Mycobacterium tuberculosis

et al. 2013

Cell Res

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Section: Dear Editormentioning

confidence: 99%

Crystal structure of L,D-transpeptidase LdtMt2 in complex with meropenem reveals the mechanism of carbapenem against Mycobacterium tuberculosis

et al. 2013

Cell Res

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“…During the course of treatment, the pathogen develops resistance against these drugs which results in Multi-Drug resistant Tuberculosis (MDR TB) and eventually lead to untreatable extensively drug resistant Tuberculosis (XDR TB) [10]. To overcome the problem of growing drug resistance, identification of new targets which are essential for survival and replication of the pathogen has become an urgent need.…”

Section: Introductionmentioning

confidence: 99%

Structural insights into mode of actions of novel natural Mycobacterium protein tyrosine phosphatase B inhibitors

et al. 2014

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BackgroundTuberculosis has become a major health problem being the second leading cause of death worldwide. Mycobacterium tuberculosis secretes a virulence factor, protein tyrosine phosphatase B (mPTPB) in the cytoplasm of host macrophage which suppresses its natural innate immune response and helps the pathogen survive and proliferate in the phagosome. The present study aims at indentifying potent inhibitors of mPTPB by using computational approaches of ligand based molecular modeling and docking studies.ResultsA 3D QSAR model was developed using a set of benzofuran salicylic acid based mPTPB inhibitors with experimentally known IC50 values. The model was generated using the statistical method of principle component regression analysis in combination with step wise forward variable selection algorithm. It was observed that steric and hydrophobic descriptors positively contribute towards the inhibitory activity of the ligands. The developed model had a robust internal as well as external predictive power as indicated by the q2 value of 0.8920 and predicted r2 value of 0.8006 respectively. Hence, the generated model was used to screen a large set of naturally occurring chemical compounds and predict their biological activity to identify more potent natural compounds targeting mPTPB. The two top potential hits (with pIC50 value of 1.459 and 1.677 respectively) had a similar interaction pattern as that of the most potent compound (pIC50 = 1.42) of the congeneric series.ConclusionThe contour plot provided a better understanding of the relationship between structural features of substituted benzofuran salicylic acid derivatives and their activities which would facilitate design of novel mPTPB inhibitors. The QSAR modeling was used to obtain an equation, correlating the important steric and hydrophobic descriptors with the pIC50 value. Thus, we report two natural compounds of inhibitory nature active against mPTPB enzyme of Mycobacterium tuberculosis. These inhibitors have the potential to evolve as lead molecules in the development of drugs for the treatment of tuberculosis.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-S1-S3) contains supplementary material, which is available to authorized users.

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“…HIV), population ageing and changes in social patterns are leading to increasing rates of disease activation (Lönnroth et al, 2009). Furthermore, drug-resistance acquisition is also becoming a concern, and reports of bacteria resistant to first and second-lines drugs are growing considerably (Gandhi et al, 2010). Thus, detailed knowledge of MTBC genetic diversity and geographical distribution is becoming of increasing importance.…”

Section: Introductionmentioning

confidence: 99%

SNP typing reveals similarity in Mycobacterium tuberculosis genetic diversity between Portugal and Northeast Brazil

Lopes

Marques

Soares

et al. 2013

Infection, Genetics and Evolution

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Abstract:Human tuberculosis is an infectious disease caused by bacteria from the Mycobacterium tuberculosis complex (MTBC). Although Spoligotyping and MIRU-VNTR are standard methodology in MTBC genetic epidemiology, recent studies suggest that Single Nucleotide Polymorphisms (SNP) are advantageous in phylogenetics and strain identification. In this work we use a set of 79 SNPs to characterize 1915 MTBC isolates from Portugal and 141 from Northeast Brazil. All Brazilian samples and a subset of 111 Portuguese isolates were further characterized using Spolygotyping. Phylogenetic analysis against a reference set revealed that about 95% of the isolates in both populations were singly attributed to bacterial lineage 4. Within this lineage, the most frequent strain groups in both Portugal and Brazil were LAM, followed by Haarlem and then X. Contrarily to these groups, strain group T showed a very different prevalence between Portugal and Brazil, with a frequency of 7% and less than 1.5%, respectively. Taking the classification by SNPs as the most accurate, we analyze the performance of Spoligotyping in strain identification. The former marker shows about 12% of miss-matches and less than 1% of unidentifiable strains. The miss-matches are observed in the most represented groups of our sample set (i.e., LAM, Haarlem and T) in almost the same proportion. Besides being more accurate in strain identification, SNPs typing can also provide phylogenetic relationships between the strain groups. Indeed, using this molecular markers we were able to observe possible signs of rare recombination events in Mtb.Overall, the use of SNP typing revealed striking similarities between MTBC populations from Portugal and Brazil. In addition this marker suggest that, albeit rare, recombination events in MTBC are likely to occur.

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Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis

Cited by 896 publications

References 103 publications

Crystal structure of L,D-transpeptidase LdtMt2 in complex with meropenem reveals the mechanism of carbapenem against Mycobacterium tuberculosis

Crystal structure of L,D-transpeptidase LdtMt2 in complex with meropenem reveals the mechanism of carbapenem against Mycobacterium tuberculosis

Structural insights into mode of actions of novel natural Mycobacterium protein tyrosine phosphatase B inhibitors

SNP typing reveals similarity in Mycobacterium tuberculosis genetic diversity between Portugal and Northeast Brazil

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