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Proc Natl Acad Sci USA. Nonsteroidal anti-inflammatory drug sensitizes Mycobacterium tuberculosis to endogenous and exogenous antimicrobials
[Source: Proceedings of the National Academy of the Sciences of the United States of America, full page: (LINK). Abstract, edited.]
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Nonsteroidal anti-inflammatory drug sensitizes Mycobacterium tuberculosis to endogenous and exogenous antimicrobials
Ben Gold<SUP>a</SUP>, Maneesh Pingle<SUP>a</SUP>, Steven J. Brickner<SUP>b</SUP>, Nilesh Shah<SUP>c</SUP>, Julia Roberts<SUP>a</SUP>, Mark Rundell<SUP>a</SUP>, W. Clay Bracken<SUP>d</SUP>, Thulasi Warrier<SUP>a</SUP>, Selin Somersan<SUP>e</SUP>, Aditya Venugopal<SUP>a</SUP>, Crystal Darby<SUP>a</SUP>, Xiuju Jiang<SUP>a</SUP>, J. David Warren<SUP>d</SUP>,<SUP>f</SUP>, Joseph Fernandez<SUP>g</SUP>, Ouathek Ouerfelli<SUP>c</SUP>, Eric L. Nuermberger<SUP>h</SUP>, Amy Cunningham-Bussel<SUP>a</SUP>, Poonam Rath<SUP>a</SUP>, Tamutenda Chidawanyika<SUP>a</SUP>, Haiteng Deng<SUP>g</SUP>, Ronald Realubit<SUP>i</SUP>, J. Fraser Glickman<SUP>i</SUP>, and Carl F. Nathan<SUP>a</SUP>,<SUP>1</SUP>
<SUP></SUP>
Author Affiliations: Departments of <SUP>a</SUP>Microbiology and Immunology, <SUP>d</SUP>Biochemistry, and <SUP>e</SUP>Medicine, and <SUP>f</SUP>Milstein Chemistry Core Facility, Weill Cornell Medical College, New York, NY 10065; <SUP>b</SUP>S. J. Brickner Consulting, LLC, Ledyard, CT 06339; <SUP>c</SUP>Organic Synthesis Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065; <SUP>h</SUP>Department of Medicine, Johns Hopkins Hospital, Baltimore, MD 21287; and <SUP>g</SUP>Proteomics Resource Center and <SUP>i</SUP>High-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)
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.
Footnotes
<SUP>1</SUP>To whom correspondence should be addressed. E-mail: cnathan@med.cornell.edu.
This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2011.
Author contributions: B.G. and C.F.N. designed research; B.G., M.P., J.R., M.R., W.C.B., T.W., S.S., A.V., C.D., X.J., J.D.W., J.F., E.L.N., A.C.-B., P.R., T.C., H.D., and R.R. performed research; N.S. and O.O. contributed new reagents/analytic tools; B.G., M.P., S.J.B., W.C.B., J.F., H.D., J.F.G., and C.F.N. analyzed data; and B.G. and C.F.N. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1214188109/-/DCSupplemental.
Freely available online through the PNAS open access option.
-<SUP></SUP>
Author Affiliations: Departments of <SUP>a</SUP>Microbiology and Immunology, <SUP>d</SUP>Biochemistry, and <SUP>e</SUP>Medicine, and <SUP>f</SUP>Milstein Chemistry Core Facility, Weill Cornell Medical College, New York, NY 10065; <SUP>b</SUP>S. J. Brickner Consulting, LLC, Ledyard, CT 06339; <SUP>c</SUP>Organic Synthesis Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065; <SUP>h</SUP>Department of Medicine, Johns Hopkins Hospital, Baltimore, MD 21287; and <SUP>g</SUP>Proteomics Resource Center and <SUP>i</SUP>High-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)
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.
Footnotes
<SUP>1</SUP>To whom correspondence should be addressed. E-mail: cnathan@med.cornell.edu.
This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2011.
Author contributions: B.G. and C.F.N. designed research; B.G., M.P., J.R., M.R., W.C.B., T.W., S.S., A.V., C.D., X.J., J.D.W., J.F., E.L.N., A.C.-B., P.R., T.C., H.D., and R.R. performed research; N.S. and O.O. contributed new reagents/analytic tools; B.G., M.P., S.J.B., W.C.B., J.F., H.D., J.F.G., and C.F.N. analyzed data; and B.G. and C.F.N. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1214188109/-/DCSupplemental.
Freely available online through the PNAS open access option.
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