title: Antiinfectives targeting enzymes and the proton motive force.
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.
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, IL 61801;
authors.forename: Xinxin
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, IL 61801;
authors.forename: Wei
authors.identifier: http://orcid.org/0000-0002-1333-323X
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry, University of Illinois, Urbana, IL 61801;
authors.forename: Lici A
authors.initials: LA
authors.lastname: Schurig-Briccio
authors.affiliation: Department of Chemistry and Biochemistry, Ohio State University, Columbus, OH 43210;
authors.forename: Steffen
authors.initials: S
authors.lastname: Lindert
authors.affiliation: Central New York Research Corporation, Veterans Affairs Medical Center, Syracuse, NY 13210;
authors.forename: Carolyn
authors.initials: C
authors.lastname: Shoen
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523;
authors.forename: Reese
authors.initials: R
authors.lastname: Hitchings
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, IL 61801;
authors.forename: Jikun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, IL 61801;
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, IL 61801;
authors.forename: Noman
authors.initials: N
authors.lastname: Baig
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, IL 61801;
authors.forename: Tianhui
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, IL 61801;
authors.forename: Boo Kyung
authors.initials: BK
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523;
authors.forename: Dean C
authors.initials: DC
authors.lastname: Crick
authors.affiliation: Central New York Research Corporation, Veterans Affairs Medical Center, Syracuse, NY 13210;
authors.forename: Michael
authors.initials: M
authors.lastname: Cynamon
authors.affiliation: Department of Pharmacology and Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA 92093; Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA 92093; National Biomedical Computation Resource, University of California San Diego, La Jolla, CA 92093; jmccammon@ucsd.edu eo@chad.scs.uiuc.edu.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, IL 61801; Department of Biochemistry, University of Illinois, Urbana, IL 61801; Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Gennis
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, IL 61801; Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801 jmccammon@ucsd.edu eo@chad.scs.uiuc.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D055592:Biophysical Phenomena; D002996:Clomiphene / Q000494:pharmacology; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D010880:Piperidines / Q000494:pharmacology; D018892:Proton-Motive Force / Q000187:drug effects*; D011804:Quinolines / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D014475:Uncoupling Agents / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; D010880:Piperidines; D011804:Quinolines; D014475:Uncoupling Agents; C000588923:vacquinol-1; D002996:Clomiphene; D019883:Alkyl and Aryl Transferases; C023266:undecaprenyl pyrophosphate synthetase
keywords: bedaquiline; clofazimine; clomiphene; molecular dynamics simulations; vacquinol