Nonsteroidal anti-inflammatory drug sensitizes Mycobacterium tuberculosis to endogenous and exogenous antimicrobials
Departments ofaMicrobiology and Immunology,
fMilstein Chemistry Core Facility, Weill Cornell Medical College, New York, NY 10065;
bS. J. Brickner Consulting, LLC, Ledyard, CT 06339;
cOrganic Synthesis Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
hDepartment of Medicine, Johns Hopkins Hospital, Baltimore, MD 21287; and
gProteomics Resource Center and
iHigh-Throughput Screening Resource Center, The Rockefeller University, New York, NY 10065
Contributed by Carl F. Nathan, August 17, 2012 (sent for review May 29, 2012)
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.
After service in the British SAS Regiment the author became a physician and then an orthopaedic surgeon.
He has held professorial positions in Canada, Vietnam and the United States, practiced and taught orthopaedic surgery in three continents and in several wars.
He has extensive experience as an expert witness in court. Somewhere along the way, time was found to operate a four hundred acre mixed farm, a one hundred seat restaurant and to obtain a licence as a flying instructor.
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