Assessment of Mycobacterium tuberculosis Pantothenate Kinase Vulnerability through Target Knockdown and Mechanistically Diverse Inhibitors

Reddy, B. Kasi; Landge, Sudhir; Ravishankar, Sudha; Patil, Vikas; Shinde, Vikas; Tantry, Subramanyam J.; Kale, Manoj; Raichurkar, Anandkumar; Menasinakai, Sreenivasaiah; Mudugal, Naina Vinay; Ambady, Anisha; Ghosh, Anirban; Tunduguru, Ragadeepthi; Kaur, Parvinder; Rg, Singh; Kumar, Naveen; Srinivasan, Bharath; Sundaram, Aishwarya; Bhat, Jyothi; Sambandamurthy, Vasan K.; Björkelid, C.; Jones, T. Alwyn; Das, Kaveri; Bandodkar, Balachandra; Malolanarasimhan, Krishnan; Mukherjee, Kakoli; Ramachandran, Vasanthi

doi:10.1128/aac.00140-14

Cited by 23 publications

(37 citation statements)

References 28 publications

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“…Although panK transcript levels were reduced by ∼50% relative to wild-type in the fully repressed panK Tet-ON S conditional mutant, this was not sufficient to confer a growth phenotype. These findings are consistent with those of Reddy et al, 43 who, during the course of our study, reported that Mtb was able to grow unimpeded in the absence of detectable levels of PanK, suggesting invulnerability of this target.…”

Section: Resultssupporting

confidence: 94%

“…66 Although this is likely attributable to their physicochemical properties, 66 it may also be due to the fact that they are noncompetitive inhibitors and, as such, are predicted to be less effective at inhibiting CoA pathway flux than mixed inhibitors would be. 43 There are currently no known inhibitors of Mtb CoaBC. However, the druggability of the CoaBC homologue from Staphylococcus aureus was confirmed by Strauss and colleagues, who showed that the natural product, CJ-15,801 is converted into a tight-binding inhibitor of the 4′-phosphopantothenoyl- l -cysteine synthetase activity of CoaBC through activation by the S. aureus type II PanK.…”

Section: Discussionmentioning

confidence: 99%

“…9,13,38−41 However, despite resource-intensive efforts that led to the identification of potent inhibitors of Mtb PanC and PanK enzymes, these molecules failed to translate into lead compounds with significant whole-cell activity. 13,42,43 Using cKD mutants of Mtb as tools to assess target vulnerability and the target selectivity of small-molecule inhibitors in whole Mtb cells, we 21 and others 43 concluded that these failures might be explained, at least in part, by the relative invulnerability of Mtb to depletion of PanC and PanK.…”

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confidence: 90%

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Validation of CoaBC as a Bactericidal Target in the Coenzyme A Pathway of Mycobacterium tuberculosis

et al. 2016

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Mycobacterium tuberculosis relies on its own ability to biosynthesize coenzyme A to meet the needs of the myriad enzymatic reactions that depend on this cofactor for activity. As such, the essential pantothenate and coenzyme A biosynthesis pathways have attracted attention as targets for tuberculosis drug development. To identify the optimal step for coenzyme A pathway disruption in M. tuberculosis, we constructed and characterized a panel of conditional knockdown mutants in coenzyme A pathway genes. Here, we report that silencing of coaBC was bactericidal in vitro, whereas silencing of panB, panC, or coaE was bacteriostatic over the same time course. Silencing of coaBC was likewise bactericidal in vivo, whether initiated at infection or during either the acute or chronic stages of infection, confirming that CoaBC is required for M. tuberculosis to grow and persist in mice and arguing against significant CoaBC bypass via transport and assimilation of host-derived pantetheine in this animal model. These results provide convincing genetic validation of CoaBC as a new bactericidal drug target.

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Section: Resultssupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 90%

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Validation of CoaBC as a Bactericidal Target in the Coenzyme A Pathway of Mycobacterium tuberculosis

et al. 2016

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“…Indeed, a panK conditional knockdown strain did not show significant attenuation in a mouse infection model even in the absence of inducer, which means that inactivation of pantothenate biosynthesis is not immediately bactericidal and that PanK is not a good drug target (94). Whether the CoA biosynthetic pathway harbors any viable drug targets remains to be assessed.…”

Section: Tuberculosis’s In Vivo Growth Requirementsmentioning

confidence: 99%

Mycobacterium tuberculosis in the Face of Host-Imposed Nutrient Limitation

Berney

Berney-Meyer

2017

Microbiol Spectr

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Coevolution of pathogens and host has led to many metabolic strategies employed by intracellular pathogens to deal with the immune response and the scarcity of food during infection. Simply put, bacterial pathogens are just looking for food. As a consequence, the host has developed strategies to limit nutrients for the bacterium by containment of the intruder in a pathogen-containing vacuole and/or by actively depleting nutrients from the intracellular space, a process called nutritional immunity. Since metabolism is a prerequisite for virulence, such pathways could potentially be good targets for antimicrobial therapies. In this chapter, we review the current knowledge about the in vivo diet of Mycobacterium tuberculosis, with a focus on amino acid and cofactors, discuss evidence for the bacilli’s nutritionally independent lifestyle in the host, and evaluate strategies for new chemotherapeutic interventions.

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“…Interestingly, recent work from our laboratory has shown that pantothenate auxotrophy is bacteriostatic for prolonged periods in unsupplemented standard medium, indicating that the consumption of this vitamin is very slow and/or that it can be efficiently recycled (57; M. Berney, unpublished results). Indeed, a panK conditional knockdown strain did not show significant attenuation in a mouse infection model even in the absence of inducer, which means that inactivation of pantothenate biosynthesis is not immediately bactericidal and that PanK is not a good drug target (94). Whether the CoA biosynthetic pathway harbors any viable drug targets remains to be assessed.…”

Section: Pantothenate (Vitamin B 5 )mentioning

confidence: 99%

Mycobacterium tuberculosisin the Face of Host-Imposed Nutrient Limitation

Berney

Berney-Meyer

2017

Tuberculosis and the Tubercle Bacillus

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Coevolution of pathogens and host has led to many metabolic strategies employed by intracellular pathogens to deal with the immune response and the scarcity of food during infection. Simply put, bacterial pathogens are just looking for food. As a consequence, the host has developed strategies to limit nutrients for the bacterium by containment of the intruder in a pathogen-containing vacuole and/or by actively depleting nutrients from the intracellular space, a process called nutritional immunity. Since metabolism is a prerequisite for virulence, such pathways could potentially be good targets for antimicrobial therapies. In this chapter, we review the current knowledge about the in vivo diet of Mycobacterium tuberculosis, with a focus on amino acid and cofactors, discuss evidence for the bacilli's nutritionally independent lifestyle in the host, and evaluate strategies for new chemotherapeutic interventions.

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Assessment of Mycobacterium tuberculosis Pantothenate Kinase Vulnerability through Target Knockdown and Mechanistically Diverse Inhibitors

Cited by 23 publications

References 28 publications

Validation of CoaBC as a Bactericidal Target in the Coenzyme A Pathway of Mycobacterium tuberculosis

Validation of CoaBC as a Bactericidal Target in the Coenzyme A Pathway of Mycobacterium tuberculosis

Mycobacterium tuberculosis in the Face of Host-Imposed Nutrient Limitation

Mycobacterium tuberculosisin the Face of Host-Imposed Nutrient Limitation

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