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A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy.


ABSTRACT: Candidate antibacterials are usually identified on the basis of their in vitro activity. However, the apparent inhibitory activity of new leads can be misleading because most culture media do not reproduce an environment relevant to infection in vivo. In this study, while screening for novel anti-tuberculars, we uncovered how carbon metabolism can affect antimicrobial activity. Novel pyrimidine-imidazoles (PIs) were identified in a whole-cell screen against Mycobacterium tuberculosis. Lead optimization generated in vitro potent derivatives with desirable pharmacokinetic properties, yet without in vivo efficacy. Mechanism of action studies linked the PI activity to glycerol metabolism, which is not relevant for M. tuberculosis during infection. PIs induced self-poisoning of M. tuberculosis by promoting the accumulation of glycerol phosphate and rapid ATP depletion. This study underlines the importance of understanding central bacterial metabolism in vivo and of developing predictive in vitro culture conditions as a prerequisite for the rational discovery of new antibiotics.

SUBMITTER: Pethe K 

PROVIDER: S-EPMC3220188 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy.

Pethe Kevin K   Sequeira Patricia C PC   Agarwalla Sanjay S   Rhee Kyu K   Kuhen Kelli K   Phong Wai Yee WY   Patel Viral V   Beer David D   Walker John R JR   Duraiswamy Jeyaraj J   Jiricek Jan J   Keller Thomas H TH   Chatterjee Arnab A   Tan Mai Ping MP   Ujjini Manjunatha M   Rao Srinivasa P S SP   Camacho Luis L   Bifani Pablo P   Mak Puiying A PA   Ma Ida I   Barnes S Whitney SW   Chen Zhong Z   Plouffe David D   Thayalan Pamela P   Ng Seow Hwee SH   Au Melvin M   Lee Boon Heng BH   Tan Bee Huat BH   Ravindran Sindhu S   Nanjundappa Mahesh M   Lin Xiuhua X   Goh Anne A   Lakshminarayana Suresh B SB   Shoen Carolyn C   Cynamon Michael M   Kreiswirth Barry B   Dartois Veronique V   Peters Eric C EC   Glynne Richard R   Brenner Sydney S   Dick Thomas T  

Nature communications 20100824


Candidate antibacterials are usually identified on the basis of their in vitro activity. However, the apparent inhibitory activity of new leads can be misleading because most culture media do not reproduce an environment relevant to infection in vivo. In this study, while screening for novel anti-tuberculars, we uncovered how carbon metabolism can affect antimicrobial activity. Novel pyrimidine-imidazoles (PIs) were identified in a whole-cell screen against Mycobacterium tuberculosis. Lead optim  ...[more]

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