Nonsteroidal anti-inflammatory drug sensitizes Mycobacterium tuberculosis to endogenous and exogenous antimicrobials. Academic Article uri icon

Overview

MeSH

  • Animals
  • Chromatography, High Pressure Liquid
  • Fatty Acids
  • Female
  • Hydroxylation
  • Magnetic Resonance Spectroscopy
  • Mice
  • Microbial Sensitivity Tests
  • Reactive Nitrogen Species

MeSH Major

  • Anti-Inflammatory Agents, Non-Steroidal
  • Drug Resistance, Microbial
  • High-Throughput Screening Assays
  • Mycobacterium tuberculosis
  • Oxyphenbutazone

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.

publication date

  • October 2, 2012

has subject area

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal
  • Chromatography, High Pressure Liquid
  • Drug Resistance, Microbial
  • Fatty Acids
  • Female
  • High-Throughput Screening Assays
  • Hydroxylation
  • Magnetic Resonance Spectroscopy
  • Mice
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis
  • Oxyphenbutazone
  • Reactive Nitrogen Species

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3479555

Digital Object Identifier (DOI)

  • 10.1073/pnas.1214188109

PubMed ID

  • 23012453

Additional Document Info

start page

  • 16004

end page

  • 16011

volume

  • 109

number

  • 40