| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Hitchings, Reese Gennis, Robert B. Mccammon, J. Andrew Li, Jikun Baig, Noman Feng, Xinxin Oldfield, Eric Wang, Yang Shoen, Carolyn Zhou, Tianhui Zhu, Wei Schurig-briccio, Lici A. Kim, Boo Kyung Cynamon, Michael Lindert, Steffen Crick, Dean C. |
| Description |
Author Affiliation: Feng X ( Department of Chemistry, University of Illinois, Urbana, IL 61801); Zhu W ( Department of Chemistry, University of Illinois, Urbana, IL 61801); Schurig-Briccio LA ( Department of Biochemistry, University of Illinois, Urbana, IL 61801); Lindert S ( Department of Chemistry and Biochemistry, Ohio State University, Columbus, OH 43210); Shoen C ( Central New York Research Corporation, Veterans Affairs Medical Center, Syracuse, NY 13210); Hitchings R ( Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523); Li J ( Department of Chemistry, University of Illinois, Urbana, IL 61801); Wang Y ( Department of Chemistry, University of Illinois, Urbana, IL 61801); Baig N ( Department of Chemistry, University of Illinois, Urbana, IL 61801); Zhou T ( Department of Chemistry, University of Illinois, Urbana, IL 61801); Kim BK ( Department of Chemistry, University of Illinois, Urbana, IL 61801); Crick DC ( Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523); Cynamon M ( Central New York Research Corporation, Veterans Affairs Medical Center, Syracuse, NY 13210); McCammon JA ( Department of Pharmacology and Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA 92093); Gennis RB ( Department of Chemistry, University of Illinois, Urbana, IL 61801); Oldfield E ( Department of Chemistry, University of Illinois, Urbana, IL 61801); |
| Abstract |
There is a growing need for new antibiotics. Compounds that target the proton motive force (PMF), uncouplers, represent one possible class of compounds that might be developed because they are already used to treat parasitic infections, and there is interest in their use for the treatment of other diseases, such as diabetes. Here, we tested a series of compounds, most with known antiinfective activity, for uncoupler activity. Many cationic amphiphiles tested positive, and some targeted isoprenoid biosynthesis or affected lipid bilayer structure. As an example, we found that clomiphene, a recently discovered undecaprenyl diphosphate synthase inhibitor active against Staphylococcus aureus, is an uncoupler. Using in silico screening, we then found that the anti-glioblastoma multiforme drug lead vacquinol is an inhibitor of Mycobacterium tuberculosis tuberculosinyl adenosine synthase, as well as being an uncoupler. Because vacquinol is also an inhibitor of M. tuberculosis cell growth, we used similarity searches based on the vacquinol structure, finding analogs with potent (â ¼0.5-2 µg/mL) activity against M. tuberculosis and S. aureus. Our results give a logical explanation of the observation that most new tuberculosis drug leads discovered by phenotypic screens and genome sequencing are highly lipophilic (logP â ¼5.7) bases with membrane targets because such species are expected to partition into hydrophobic membranes, inhibiting membrane proteins, in addition to collapsing the PMF. This multiple targeting is expected to be of importance in overcoming the development of drug resistance because targeting membrane physical properties is expected to be less susceptible to the development of resistance. |
| ISSN |
00278424 |
| e-ISSN |
10916490 |
| Journal |
Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number |
51 |
| Volume Number |
112 |
| Language |
English |
| Publisher |
National Academy of Sciences |
| Publisher Date |
2015-12-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Anti-Infective Agents Pharmacology Proton-Motive Force Drug Effects Uncoupling Agents Alkyl And Aryl Transferases Antagonists & Inhibitors Chemistry Biophysical Phenomena Clomiphene Drug Discovery Enzyme Inhibitors Models, Molecular Molecular Dynamics Simulation Molecular Structure Mycobacterium Tuberculosis Enzymology Growth & Development Piperidines Quinolines Staphylococcus Aureus Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Multidisciplinary |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Multidisciplinary |
