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 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.
authors.affiliation: Department of Microbiology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Gold
authors.forename: Maneesh
authors.initials: M
authors.lastname: Pingle
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Brickner
authors.forename: Nilesh
authors.initials: N
authors.lastname: Shah
authors.forename: Julia
authors.initials: J
authors.lastname: Roberts
authors.forename: Mark
authors.initials: M
authors.lastname: Rundell
authors.forename: W Clay
authors.initials: WC
authors.lastname: Bracken
authors.forename: Thulasi
authors.initials: T
authors.lastname: Warrier
authors.forename: Selin
authors.initials: S
authors.lastname: Somersan
authors.forename: Aditya
authors.initials: A
authors.lastname: Venugopal
authors.forename: Crystal
authors.initials: C
authors.lastname: Darby
authors.forename: Xiuju
authors.initials: X
authors.lastname: Jiang
authors.forename: J David
authors.initials: JD
authors.lastname: Warren
authors.forename: Joseph
authors.initials: J
authors.lastname: Fernandez
authors.forename: Ouathek
authors.initials: O
authors.lastname: Ouerfelli
authors.forename: Eric L
authors.initials: EL
authors.lastname: Nuermberger
authors.forename: Amy
authors.initials: A
authors.lastname: Cunningham-Bussel
authors.forename: Poonam
authors.initials: P
authors.lastname: Rath
authors.forename: Tamutenda
authors.initials: T
authors.lastname: Chidawanyika
authors.forename: Haiteng
authors.initials: H
authors.lastname: Deng
authors.forename: Ronald
authors.initials: R
authors.lastname: Realubit
authors.forename: J Fraser
authors.initials: JF
authors.lastname: Glickman
authors.forename: Carl F
authors.initials: CF
authors.lastname: Nathan
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004352:Drug Resistance, Microbial / Q000187:drug effects* / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D057166:High-Throughput Screening Assays / Q000379:methods*; D006900:Hydroxylation; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000502:physiology; D010113:Oxyphenbutazone / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D026361:Reactive Nitrogen Species / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005227:Fatty Acids; D026361:Reactive Nitrogen Species; D010113:Oxyphenbutazone