-
Tuberculosis (Edinburgh, Scotland) Mar 2011The TB Structural Genomics Consortium is a worldwide organization of collaborators whose mission is the comprehensive structural determination and analyses of... (Review)
Review
The TB Structural Genomics Consortium is a worldwide organization of collaborators whose mission is the comprehensive structural determination and analyses of Mycobacterium tuberculosis proteins to ultimately aid in tuberculosis diagnosis and treatment. Congruent to the overall vision, Consortium members have additionally established an integrated facilities core to streamline M. tuberculosis structural biology and developed bioinformatics resources for data mining. This review aims to share the latest Consortium developments with the TB community, including recent structures of proteins that play significant roles within M. tuberculosis. Atomic resolution details may unravel mechanistic insights and reveal unique and novel protein features, as well as important protein-protein and protein-ligand interactions, which ultimately lead to a better understanding of M. tuberculosis biology and may be exploited for rational, structure-based therapeutics design.
Topics: Bacterial Proteins; Crystallography, X-Ray; Databases, Protein; Drug Design; Genome, Bacterial; Genomics; Humans; International Cooperation; Models, Molecular; Mycobacterium tuberculosis
PubMed: 21247804
DOI: 10.1016/j.tube.2010.11.009 -
IUBMB Life Apr 2021Tuberculosis caused by the bacterium, Mycobacterium tuberculosis (Mtb), continues to remain one of the most devastating infectious diseases afflicting humans. Although... (Review)
Review
Tuberculosis caused by the bacterium, Mycobacterium tuberculosis (Mtb), continues to remain one of the most devastating infectious diseases afflicting humans. Although there are several drugs for treating tuberculosis available currently, the emergence of the drug resistant forms of this pathogen has made its treatment and eradication a challenging task. While the replication machinery, protein synthesis and cell wall biogenesis of Mtb have been targeted often for anti-tubercular drug development a number of essential metabolic pathways crucial to its survival have received relatively less attention. In this context a number of amino acid biosynthesis pathways have recently been shown to be essential for the survival and pathogenesis of Mtb. Many of these pathways and or their key enzymes homologs are absent in humans hence they could be harnessed for anti-tubercular drug development. In this review, we describe comprehensively the amino acid metabolic pathways essential in Mtb and the key enzymes involved therein that are being investigated for developing inhibitors that compromise the survival and pathogenesis caused by this pathogen.
Topics: Amino Acids; Antitubercular Agents; Mycobacterium tuberculosis
PubMed: 33624925
DOI: 10.1002/iub.2455 -
Clinical Microbiology and Infection :... Jun 2011Genotyping of Mycobacterium tuberculosis has been extensively used for investigating epidemics of multidrug-resistant strains of M. tuberculosis, in order to identify... (Review)
Review
Genotyping of Mycobacterium tuberculosis has been extensively used for investigating epidemics of multidrug-resistant strains of M. tuberculosis, in order to identify the factors involved in the transmission of such strains and determine effective control programmes to limit their expansion at both the individual and population levels. Here, we review the methods currently used to study the molecular epidemiology of multidrug-resistant M. tuberculosis strains, and the insights provided by these techniques regarding global trends and the transmission dynamics of multidrug-resistant tuberculosis at a world scale.
Topics: Antitubercular Agents; Bacterial Typing Techniques; Drug Resistance, Multiple, Bacterial; Genotype; Humans; Molecular Epidemiology; Molecular Typing; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 21682800
DOI: 10.1111/j.1469-0691.2011.03577.x -
Clinical Microbiology and Infection :... Jun 2011Mycobacterium tuberculosis harbours little DNA sequence diversity compared with other bacteria. However, there is mounting evidence that strain-to-strain variation in... (Review)
Review
Mycobacterium tuberculosis harbours little DNA sequence diversity compared with other bacteria. However, there is mounting evidence that strain-to-strain variation in this organism has been underestimated. We review our current understanding of the genetic diversity among M. tuberculosis clinical strains and discuss the relevance of this diversity for the ongoing global epidemics of drug-resistant tuberculosis. Based on findings in other bacteria, we propose that epistatic interactions between pre-existing differences in strain genetic background, acquired drug-resistance-conferring mutations and compensatory changes could play a role in the emergence and spread of drug-resistant M. tuberculosis.
Topics: Antitubercular Agents; Drug Resistance, Bacterial; Epistasis, Genetic; Evolution, Molecular; Genotype; Humans; Molecular Epidemiology; Mycobacterium tuberculosis; Polymorphism, Genetic; Tuberculosis
PubMed: 21682802
DOI: 10.1111/j.1469-0691.2011.03556.x -
MBio Apr 2017Drug-resistant mycobacterial infections are a serious global health challenge, leading to high mortality and socioeconomic burdens in developing countries worldwide. New... (Review)
Review
Drug-resistant mycobacterial infections are a serious global health challenge, leading to high mortality and socioeconomic burdens in developing countries worldwide. New innovative approaches, from identification of new targets to discovery of novel chemical scaffolds, are urgently needed. Recently, energy metabolism in mycobacteria, in particular the oxidative phosphorylation pathway, has emerged as an object of intense microbiological investigation and as a novel target pathway in drug discovery. New classes of antibacterials interfering with elements of the oxidative phosphorylation pathway are highly active in combating dormant or latent mycobacterial infections, with a promise of shortening tuberculosis chemotherapy. The regulatory approval of the ATP synthase inhibitor bedaquiline and the discovery of Q203, a candidate drug targeting the cytochrome complex, have highlighted the central importance of this new target pathway. In this review, we discuss key features and potential applications of inhibiting energy metabolism in our quest for discovering potent novel and sterilizing drug combinations for combating tuberculosis. We believe that the combination of drugs targeting elements of the oxidative phosphorylation pathway can lead to a completely new regimen for drug-susceptible and multidrug-resistant tuberculosis.
Topics: Antitubercular Agents; Drug Discovery; Energy Metabolism; Mycobacterium tuberculosis; Oxidative Phosphorylation
PubMed: 28400527
DOI: 10.1128/mBio.00272-17 -
MBio Aug 2020, which causes tuberculosis (TB), is estimated to infect one-third of the world's population. The overall burden and the emergence of drug-resistant strains of...
, which causes tuberculosis (TB), is estimated to infect one-third of the world's population. The overall burden and the emergence of drug-resistant strains of underscore the need for new therapeutic options against this important human pathogen. Our recent work demonstrated the success of natural product discovery in identifying novel compounds with efficacy against Here, we improve on these methods by combining improved isolation and selective screening to identify three new anti-TB compounds: streptomycobactin, kitamycobactin, and amycobactin. We were unable to obtain mutants resistant to streptomycobactin, and its target remains to be elucidated. We identify the target of kitamycobactin to be the mycobacterial ClpP1P2C1 protease and confirm that kitamycobactin is an analog of the previously identified compound lassomycin. Further, we identify the target of amycobactin to be the essential protein secretion pore SecY. We show further that amycobactin inhibits protein secretion via the SecY translocon. Importantly, this inhibition is bactericidal to nonreplicating This is the first compound, to our knowledge, that targets the Sec protein secretion machinery in This work underscores the ability of natural product discovery to deliver not only new compounds with activity against but also compounds with novel targets. Decreasing discovery rates and increasing resistance have underscored the need for novel therapeutic options to treat infection. Here, we screen extracts from previously uncultured soil microbes for specific activity against , identifying three novel compounds. We further define the mechanism of action of one compound, amycobactin, and demonstrate that it inhibits protein secretion through the Sec translocation machinery.
Topics: Antitubercular Agents; Drug Discovery; Humans; Mycobacterium tuberculosis; Protease Inhibitors; Tuberculosis
PubMed: 32753498
DOI: 10.1128/mBio.01516-20 -
Journal of Bacteriology Aug 2009
Review
Topics: Hydrogen-Ion Concentration; Macrophages; Models, Biological; Mycobacterium tuberculosis; Phagosomes
PubMed: 19465648
DOI: 10.1128/JB.00305-09 -
Microbiology Spectrum Jun 2017The emergence and spread of drug-resistant pathogens, and our inability to develop new antimicrobials to combat resistance, have inspired scientists to seek out new... (Review)
Review
The emergence and spread of drug-resistant pathogens, and our inability to develop new antimicrobials to combat resistance, have inspired scientists to seek out new targets for drug development. The complex is a group of obligately aerobic bacteria that have specialized for inhabiting a wide range of intracellular and extracellular environments. Two fundamental features in this adaptation are the flexible utilization of energy sources and continued metabolism in the absence of growth. is an obligately aerobic heterotroph that depends on oxidative phosphorylation for growth and survival. However, several studies are redefining the metabolic breadth of the genus. Alternative electron donors and acceptors may provide the maintenance energy for the pathogen to maintain viability in hypoxic, nonreplicating states relevant to latent infection. This hidden metabolic flexibility may ultimately decrease the efficacy of drugs targeted against primary dehydrogenases and terminal oxidases. However, it may also open up opportunities to develop novel antimycobacterials targeting persister cells. In this review, we discuss the progress in understanding the role of energetic targets in mycobacterial physiology and pathogenesis and the opportunities for drug discovery.
Topics: Antitubercular Agents; Drug Discovery; Drug Resistance, Bacterial; Energy Metabolism; Mycobacterium tuberculosis; Oxidative Phosphorylation; Oxidoreductases; Tuberculosis
PubMed: 28597820
DOI: 10.1128/microbiolspec.TBTB2-0014-2016 -
Future Microbiology Oct 2010Protein export is essential in all bacteria and many bacterial pathogens depend on specialized protein export systems for virulence. In Mycobacterium tuberculosis, the... (Review)
Review
Protein export is essential in all bacteria and many bacterial pathogens depend on specialized protein export systems for virulence. In Mycobacterium tuberculosis, the etiological agent of the disease tuberculosis, the conserved general secretion (Sec) and twin-arginine translocation (Tat) pathways perform the bulk of protein export and are both essential. M. tuberculosis also has specialized export pathways that transport specific subsets of proteins. One such pathway is the accessory SecA2 system, which is important for M. tuberculosis virulence. There are also specialized ESX export systems that function in virulence (ESX-1) or essential physiologic processes (ESX-3). The increasing prevalence of drug-resistant M. tuberculosis strains makes the development of novel drugs for tuberculosis an urgent priority. In this article, we discuss our current understanding of the protein export systems of M. tuberculosis and consider the potential of these pathways to be novel targets for tuberculosis drugs.
Topics: Antitubercular Agents; Bacterial Proteins; Humans; Membrane Transport Proteins; Mycobacterium tuberculosis
PubMed: 21073315
DOI: 10.2217/fmb.10.112 -
Future Microbiology Jul 2013Most of the newly discovered compounds showing promise for the treatment of TB, notably multidrug-resistant TB, inhibit aspects of Mycobacterium tuberculosis cell... (Review)
Review
Most of the newly discovered compounds showing promise for the treatment of TB, notably multidrug-resistant TB, inhibit aspects of Mycobacterium tuberculosis cell envelope metabolism. This review reflects on the evolution of the knowledge that many of the front-line and emerging products inhibit aspects of cell envelope metabolism and in the process are bactericidal not only against actively replicating M. tuberculosis, but contrary to earlier impressions, are effective against latent forms of the disease. While mycolic acid and arabinogalactan synthesis are still primary targets of existing and new drugs, peptidoglycan synthesis, transport mechanisms and the synthesis of the decaprenyl-phosphate carrier lipid all show considerable promise as targets for new products, older drugs and new combinations. The advantages of whole cell- versus target-based screening in the perpetual search for new targets and products to counter multidrug-resistant TB are discussed.
Topics: Animals; Antitubercular Agents; Cell Wall; Drug Evaluation, Preclinical; Humans; Mycobacterium tuberculosis; Tuberculosis
PubMed: 23841633
DOI: 10.2217/fmb.13.52