Mycobacterium tuberculosis strain with deletions in menT3 and menT4 is attenuated and confers protection in mice and guinea pigs.

The genome of Mycobacterium tuberculosis encodes for a large repertoire of toxin-antitoxin systems. In the present study, MenT3 and MenT4 toxins belonging to MenAT subfamily of TA systems have been functionally characterized. We demonstrate that ectopic expression of these toxins inhibits bacterial growth and this is rescued upon co-expression of their cognate antitoxins.

Structural and Functional Characterization of Rv0792c from Mycobacterium tuberculosis: Identifying Small Molecule Inhibitor against HutC Protein.

In order to adapt in host tissues, microbial pathogens regulate their gene expression through a variety of transcription factors. Here, we have functionally characterized Rv0792c, a HutC homolog from Mycobacterium tuberculosis. In comparison to the parental strain, a strain of M.

Exopolyphosphatases PPX1 and PPX2 from Mycobacterium tuberculosis regulate dormancy response and pathogenesis.

Stress adaptation and virulence of various bacterial pathogens require stringent response pathways involving guanosine pentaphosphate and inorganic polyphosphate (PolyP). In M. tuberculosis, intracellular PolyP levels are maintained by the activities of polyphosphate kinase (PPK-1, PPK-2) and exopolyphosphatases (PPX-1, PPX-2).

Disruption of MenT2 toxin impairs the growth of in guinea pigs.

Toxin-antitoxin (TA) systems are abundantly present in the genomes of various bacterial pathogens. TA systems have been implicated in either plasmid maintenance or protection against phage infection, stress adaptation or disease pathogenesis. The genome of encodes for more than 90 TA systems and 4 of these belong to the type IV subfamily (MenAT family).

Identification of small molecules targeting homoserine acetyl transferase from Mycobacterium tuberculosis and Staphylococcus aureus.

There is an urgent need to validate new drug targets and identify small molecules that possess activity against both drug-resistant and drug-sensitive bacteria. The enzymes belonging to amino acid biosynthesis have been shown to be essential for growth in vitro, in vivo and have not been exploited much for the development of anti-tubercular agents. Here, we have identified small molecule inhibitors targeting homoserine acetyl transferase (HSAT, MetX, Rv3341) from M.

Functional and Biochemical Characterization of the MazEF6 Toxin-Antitoxin System of Mycobacterium tuberculosis.

The Mycobacterium tuberculosis genome harbors nine toxin-antitoxin (TA) systems that are members of the family, unlike other prokaryotes, which have only one or two. Although the overall tertiary folds of MazF toxins are predicted to be similar, it is unclear how they recognize structurally different RNAs and antitoxins with divergent sequence specificity. Here, we have expressed and purified the individual components and complex of the MazEF6 TA system from M.

HigB1 Toxin in Is Upregulated During Stress and Required to Establish Infection in Guinea Pigs.

The extraordinary expansion of Toxin Antitoxin (TA) modules in the genome of has received significant attention over the last few decades. The cumulative evidence suggests that TA systems are activated in response to stress conditions and are essential for pathogenesis. In , Rv1955-Rv1956-Rv1957 constitutes the only tripartite TAC (Toxin Antitoxin Chaperone) module.

Identification of diphenyl furan derivatives via high throughput and computational studies as ArgA inhibitors of Mycobacterium tuberculosis.

Microbial amino acid biosynthetic pathways are underexploited for the development of anti-bacterial agents. N-acetyl glutamate synthase (ArgA) catalyses the first committed step in L-arginine biosynthesis and is essential for M. tuberculosis growth.

Co-Administration of Anticancer Candidate MK-2206 Enhances the Efficacy of BCG Vaccine Against in Mice and Guinea Pigs.

The failure of BCG to induce long-term protection has been endowed to its inability to escape the phagolysosome, leading to mild activation of CD8 mediated T cell response. Induction of apoptosis in host cells plays an important role in potentiating dendritic cells-mediated priming of CD8 T cells, a process defined as "cross-priming." Moreover, IL-10 secretion by infected cells has been reported to hamper BCG-induced immunity against Tuberculosis (TB).

NSC 18725, a Pyrazole Derivative Inhibits Growth of Intracellular by Induction of Autophagy.

The increasing incident rates of drug-resistant tuberculosis (DR-TB) is a global health concern and has been further complicated by the emergence of extensive and total drug-resistant strains. Identification of new chemical entities which are compatible with first-line TB drugs, possess activity against DR-, and metabolically less active bacteria is required to tackle this epidemic. Here, we have performed phenotypic screening of a small molecule library against BCG and identified 24 scaffolds that exhibited MIC values of at least 2.

Identification and Repurposing of Trisubstituted Harmine Derivatives as Novel Inhibitors of Phosphoserine Phosphatase.

is still the deadliest bacterial pathogen worldwide and the increasing number of multidrug-resistant tuberculosis cases further complicates this global health issue. phosphoserine phosphatase SerB2 is a promising target for drug design. Besides being a key essential metabolic enzyme of the pathogen's serine pathway, it appears to be involved in immune evasion mechanisms.

NU-6027 Inhibits Growth of Mycobacterium tuberculosis by Targeting Protein Kinase D and Protein Kinase G.

Tuberculosis (TB) is a global health concern, and this situation has further worsened due to the emergence of drug-resistant strains and the failure of BCG vaccine to impart protection. There is an imperative need to develop highly sensitive, specific diagnostic tools, novel therapeutics, and vaccines for the eradication of TB. In the present study, a chemical screen of a pharmacologically active compound library was performed to identify antimycobacterial compounds.

Inorganic polyphosphate accumulation suppresses the dormancy response and virulence in .

Stringent response pathways involving inorganic polyphosphate (PolyP) play an essential role in bacterial stress adaptation and virulence. The intracellular levels of PolyP are modulated by the activities of polyphosphate kinase-1 (PPK1), polyphosphate kinase-2 (PPK2), and exopolyphosphatases (PPXs). The genome of encodes two functional PPXs, and simultaneous deletion of and results in a defect in biofilm formation.

Dual Mechanism of Action of 5-Nitro-1,10-Phenanthroline against Mycobacterium tuberculosis.

New chemotherapeutic agents with novel mechanisms of action are urgently required to combat the challenge imposed by the emergence of drug-resistant mycobacteria. In this study, a phenotypic whole-cell screen identified 5-nitro-1,10-phenanthroline (5NP) as a lead compound. 5NP-resistant isolates harbored mutations that were mapped to and were also resistant to the bicyclic nitroimidazole PA-824.