TY - JOUR
T1 - Antiinfectives targeting enzymes and the proton motive force
AU - Feng, Xinxin
AU - Zhu, Wei
AU - Schurig-Briccio, Lici A.
AU - Lindert, Steffen
AU - Shoen, Carolyn
AU - Hitchings, Reese
AU - Li, Jikun
AU - Wang, Yang
AU - Baig, Noman
AU - Zhou, Tianhui
AU - Kim, Boo Kyung
AU - Crick, Dean C.
AU - Cynamon, Michael
AU - McCammon, J. Andrew
AU - Gennis, Robert B.
AU - Oldfield, Eric
N1 - Funding Information:
We thank Prof. Tsutomu Hoshino for providing tuberculosinyl diphosphate and Prof. David B. Moody for his helpful comments. This work was supported by the US Public Health Service (NIH Grant GM065307), by a Harriet A. Harlin Professorship (to E.O.), and by the University of Illinois Foundation/Oldfield Research Fund. Work at the University of California San Diego was supported, in part, by the NIH, National Science Foundation, Howard Hughes Medical Institute, the National Biomedical Computation Resource (NBCR), and the San Diego Supercomputer Center (SDSC).
PY - 2015/12/22
Y1 - 2015/12/22
N2 - 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.
AB - 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.
KW - Bedaquiline
KW - Clofazimine
KW - Clomiphene
KW - Molecular dynamics simulations
KW - Vacquinol
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U2 - 10.1073/pnas.1521988112
DO - 10.1073/pnas.1521988112
M3 - Article
C2 - 26644565
AN - SCOPUS:84952671080
SN - 0027-8424
VL - 112
SP - E7073-E7082
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 51
ER -