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

Kevin Pethe (), Patricia C. Sequeira, Sanjay Agarwalla, Kyu Rhee, Kelli Kuhen, Wai Yee Phong, Viral Patel, David Beer, John R. Walker, Jeyaraj Duraiswamy, Jan Jiricek, Thomas H. Keller, Arnab Chatterjee, Mai Ping Tan, Manjunatha Ujjini, Srinivasa P.S. Rao, Luis Camacho, Pablo Bifani, Puiying A. Mak, Ida Ma, S. Whitney Barnes, Zhong Chen, David Plouffe, Pamela Thayalan, Seow Hwee Ng, Melvin Au, Boon Heng Lee, Bee Huat Tan, Sindhu Ravindran, Mahesh Nanjundappa, Xiuhua Lin, Anne Goh, Suresh B. Lakshminarayana, Carolyn Shoen, Michael Cynamon, Barry Kreiswirth, Veronique Dartois, Eric C. Peters, Richard Glynne, Sydney Brenner and Thomas Dick
Additional contact information
Kevin Pethe: Novartis Institute for Tropical Diseases, #05-01 Chromos
Patricia C. Sequeira: Novartis Institute for Tropical Diseases, #05-01 Chromos
Sanjay Agarwalla: Genomics Institute of the Novartis Research Foundation
Kyu Rhee: Weill Cornell Medical College
Kelli Kuhen: Genomics Institute of the Novartis Research Foundation
Wai Yee Phong: Novartis Institute for Tropical Diseases, #05-01 Chromos
Viral Patel: Novartis Institute for Tropical Diseases, #05-01 Chromos
David Beer: Novartis Institute for Tropical Diseases, #05-01 Chromos
John R. Walker: Genomics Institute of the Novartis Research Foundation
Jeyaraj Duraiswamy: Novartis Institute for Tropical Diseases, #05-01 Chromos
Jan Jiricek: Novartis Institute for Tropical Diseases, #05-01 Chromos
Thomas H. Keller: Novartis Institute for Tropical Diseases, #05-01 Chromos
Arnab Chatterjee: Genomics Institute of the Novartis Research Foundation
Mai Ping Tan: Novartis Institute for Tropical Diseases, #05-01 Chromos
Manjunatha Ujjini: Novartis Institute for Tropical Diseases, #05-01 Chromos
Srinivasa P.S. Rao: Novartis Institute for Tropical Diseases, #05-01 Chromos
Luis Camacho: Novartis Institute for Tropical Diseases, #05-01 Chromos
Pablo Bifani: Novartis Institute for Tropical Diseases, #05-01 Chromos
Puiying A. Mak: Genomics Institute of the Novartis Research Foundation
Ida Ma: Novartis Institute for Tropical Diseases, #05-01 Chromos
S. Whitney Barnes: Genomics Institute of the Novartis Research Foundation
Zhong Chen: Genomics Institute of the Novartis Research Foundation
David Plouffe: Genomics Institute of the Novartis Research Foundation
Pamela Thayalan: Novartis Institute for Tropical Diseases, #05-01 Chromos
Seow Hwee Ng: Novartis Institute for Tropical Diseases, #05-01 Chromos
Melvin Au: Novartis Institute for Tropical Diseases, #05-01 Chromos
Boon Heng Lee: Novartis Institute for Tropical Diseases, #05-01 Chromos
Bee Huat Tan: Novartis Institute for Tropical Diseases, #05-01 Chromos
Sindhu Ravindran: Novartis Institute for Tropical Diseases, #05-01 Chromos
Mahesh Nanjundappa: Novartis Institute for Tropical Diseases, #05-01 Chromos
Xiuhua Lin: Novartis Institute for Tropical Diseases, #05-01 Chromos
Anne Goh: Novartis Institute for Tropical Diseases, #05-01 Chromos
Suresh B. Lakshminarayana: Novartis Institute for Tropical Diseases, #05-01 Chromos
Carolyn Shoen: Veterans Affairs Medical Center
Michael Cynamon: Veterans Affairs Medical Center
Barry Kreiswirth: Public Health Research Institute
Veronique Dartois: Novartis Institute for Tropical Diseases, #05-01 Chromos
Eric C. Peters: Genomics Institute of the Novartis Research Foundation
Richard Glynne: Genomics Institute of the Novartis Research Foundation
Sydney Brenner: Molecular Engineering Laboratory, Science and Engineering Institute, Agency for Science Technology and Research
Thomas Dick: Novartis Institute for Tropical Diseases, #05-01 Chromos

Nature Communications, 2010, vol. 1, issue 1, 1-8

Abstract: 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.

Date: 2010
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DOI: 10.1038/ncomms1060

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