Oxadiazoles Have Butyrate-Specific Conditional Activity against Mycobacterium tuberculosis

Author:

Early Julie V.1,Casey Allen1,Martinez-Grau Maria Angeles2,Gonzalez Valcarcel Isabel C.3,Vieth Michal3,Ollinger Juliane1,Bailey Mai Ann1,Alling Torey1,Files Megan1,Ovechkina Yulia1,Parish Tanya1

Affiliation:

1. TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, USA

2. Eli Lilly and Company, Alcobendas, Madrid, Spain

3. Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA

Abstract

ABSTRACT Mycobacterium tuberculosis is a global pathogen of huge importance which can adapt to several host niche environments in which carbon source availability is likely to vary. We developed and ran a phenotypic screen using butyrate as the sole carbon source to be more reflective of the host lung environment. We screened a library of ∼87,000 small compounds and identified compounds which demonstrated good antitubercular activity against M. tuberculosis grown with butyrate but not with glucose as the carbon source. Among the hits, we identified an oxadiazole series (six compounds) which had specific activity against M. tuberculosis but which lacked cytotoxicity against mammalian cells.

Funder

Lilly TB Drug Discovery Initiative

Bill and Melinda Gates Foundation

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

Reference54 articles.

1. World Health Organization. 2016. Tuberculosis fact sheet no. 104. World Health Organization Geneva Switzerland. http://www.who.int/mediacentre/factsheets/fs104/en/.

2. World Health Organization. 2015. World health statistics 2015. World Health Organization, Geneva, Switzerland.

3. Central carbon metabolism in Mycobacterium tuberculosis: an unexpected frontier

4. Metabolomics of Mycobacterium tuberculosis Reveals Compartmentalized Co-Catabolism of Carbon Substrates

5. Glucose Phosphorylation Is Required for Mycobacterium tuberculosis Persistence in Mice

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