Nonsteroidal anti-inflammatory drug sensitizes Mycobacterium tuberculosis to endogenous and exogenous antimicrobials Journal Article
| Authors: | Gold, B.; Pingle, M.; Brickner, S. J.; Shah, N.; Roberts, J.; Rundell, M.; Bracken, W. C.; Warrier, T.; Somersan, S.; Venugopal, A.; Darby, C.; Jiang, X.; Warren, J. D.; Fernandez, J.; Ouerfelli, O.; Nuermberger, E. L.; Cunningham-Bussel, A.; Rath, P.; Chidawanyika, T.; Deng, H.; Realubit, R.; Fraser Glickman, J.; Nath, C. F. |
| Article Title: | Nonsteroidal anti-inflammatory drug sensitizes Mycobacterium tuberculosis to endogenous and exogenous antimicrobials |
| 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. |
| Keywords: | controlled study; nonhuman; mouse; animals; mice; animal experiment; animal model; high throughput screening; high-throughput screening assays; hypoxia; quercetin; mycobacterium tuberculosis; drug mechanism; anti-inflammatory agents, non-steroidal; magnetic resonance spectroscopy; fatty acids; drug blood level; chromatography, high pressure liquid; fatty acid; tuberculosis; drug exposure; acid; hydroxylation; reactive nitrogen species; minimum inhibitory concentration; bactericidal activity; drug resistance, microbial; acetylcysteine; microbial sensitivity tests; oxyphenbutazone; carbon source |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 109 |
| Issue: | 40 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2012-10-02 |
| Start Page: | 16004 |
| End Page: | 16011 |
| Language: | English |
| DOI: | 10.1073/pnas.1214188109 |
| PROVIDER: | scopus |
| PMCID: | PMC3479555 |
| PUBMED: | 23012453 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 2 November 2012" - "CODEN: PNASA" - "Source: Scopus" |
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