Nonsteroidal anti-inflammatory drug sensitizes Mycobacterium tuberculosis to endogenous and exogenous antimicrobials

Ben Gold, Maneesh Pingle, Steven J. Brickner, Nilesh Shah, Julia Roberts, Mark Rundell, W. Clay Bracken, Thulasi Warrier, Selin Somersan, Aditya Venugopal, Crystal Darby, Xiuju Jiang, J. David Warren, Joseph Fernandez, Ouathek Ouerfelli, Eric L. Nuermberger, Amy Cunningham-Bussel, Poonam Rath, Tamutenda Chidawanyika, Haiteng DengRonald Realubit, J. Fraser Glickman, Carl F. Nath

Research output: Contribution to journalArticlepeer-review

Abstract

Existing drugs are slow to eradicate Mycobacterium tuberculosis (Mtb) in patients and have failed to control tuberculosis globally. One reason may be that host conditions impair Mtb's replication, reducing its sensitivity to most antiinfectives. We devised a high-throughput screen for compounds that kill Mtb when its replication has been halted by reactive nitrogen intermediates (RNIs), acid, hypoxia, and a fatty acid carbon source. At concentrations routinely achieved in human blood, oxyphenbutazone (OPB), an inexpensive anti-inflammatory drug, was selectively mycobactericidal to nonreplicating (NR) Mtb. Its cidal activity depended on mild acid and was augmented by RNIs and fatty acid. Acid and RNIs fostered OPB's 4-hydroxylation. The resultant 4-butyl-4-hydroxy-1- (4-hydroxyphenyl)-2-phenylpyrazolidine-3,5-dione (4-OH-OPB) killed both replicating and NR Mtb, including Mtb resistant to standard drugs. 4-OH-OPB depleted flavins and formed covalent adducts with N-acetyl-cysteine and mycothiol. 4-OH-OPB killed Mtb synergistically with oxidants and several antituberculosis drugs. Thus, conditions that blockMtb's replicationmodify OPB and enhance its cidal action. Modified OPB kills both replicating and NR Mtb and sensitizes both to host-derived and medicinal antimycobacterial agents.

Original languageEnglish (US)
Pages (from-to)16004-16011
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number40
DOIs
StatePublished - Oct 2 2012

ASJC Scopus subject areas

  • General

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