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

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

  • Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):16004-11. doi: 10.1073/pnas.1214188109.
Ben Gold 1 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 Deng Ronald Realubit J Fraser Glickman Carl F Nathan
Affiliations

Affiliation

  • 1 Department of Microbiology, Weill Cornell Medical College, New York, NY 10065, USA.
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 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.

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