Antiinfectives targeting enzymes and the proton motive force

Xinxin Feng, Wei Zhu, Lici A. Schurig-Briccio, Steffen Lindert, Carolyn Shoen, Reese Hitchings, Jikun Li, Yang Wang, Noman Baig, Tianhui Zhou, Boo Kyung Kim, Dean C. Crick, Michael Cynamon, J. Andrew McCammon, Robert B. Gennis, Eric Oldfield

Research output: Contribution to journalArticle

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 (∼0.5-2 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 ∼5.7) 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.

Original languageEnglish (US)
Pages (from-to)E7073-E7082
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number51
DOIs
StatePublished - Dec 22 2015

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Keywords

  • Bedaquiline
  • Clofazimine
  • Clomiphene
  • Molecular dynamics simulations
  • Vacquinol

ASJC Scopus subject areas

  • General

Cite this

Feng, X., Zhu, W., Schurig-Briccio, L. A., Lindert, S., Shoen, C., Hitchings, R., Li, J., Wang, Y., Baig, N., Zhou, T., Kim, B. K., Crick, D. C., Cynamon, M., McCammon, J. A., Gennis, R. B., & Oldfield, E. (2015). Antiinfectives targeting enzymes and the proton motive force. Proceedings of the National Academy of Sciences of the United States of America, 112(51), E7073-E7082. https://doi.org/10.1073/pnas.1521988112