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

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...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 109; no. 4; p. 16004
Main Authors Gold, Ben, Pingle, Maneesh, Brickner, Steven J, Shah, Nilesh, Roberts, Julia, Rundell, Mark, Bracken, W Clay, Warrier, Thulasi, Somersan, Selin, Venugopal, Aditya, Darby, Crystal, Jiang, Xiuju, Warren, J David, Fernandez, Joseph, Ouerfelli, Ouathek, Nuermberger, Eric L, Cunningham-Bussel, Amy, Rath, Poonam, Chidawanyika, Tamutenda, Deng, Haiteng, Realubit, Ronald, Glickman, J Fraser, Nathan, Carl F
Format Journal Article
LanguageEnglish
Published Washington National Academy of Sciences 02.10.2012
Subjects
Antimicrobial agents
Bacteria
Chemical compounds
Drug resistance
Nonsteroidal anti-inflammatory drugs
Tuberculosis
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Summary: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 block Mtb's replication modify OPB and enhance its cidal action. Modified OPB kills both replicating and NR Mtb and sensitizes both to host-derived and medicinal antimycobacterial agents. [PUBLICATION ABSTRACT]
ISSN:0027-8424
1091-6490