Undecaprenyl diphosphate synthase inhibitors: antibacterial drug leads.
There is a significant need for new antibiotics due to the rise in drug resistance. Drugs such as methicillin and vancomycin target bacterial cell wall biosynthesis, but methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) have now arisen and are of major concern. Inhibitors acting on new targets in cell wall biosynthesis are thus of particular interest since they might also restore sensitivity to existing drugs, and the cis-prenyl transferase undecaprenyl diphosphate synthase (UPPS), essential for lipid I, lipid II, and thus, peptidoglycan biosynthesis, is one such target. We used 12 UPPS crystal structures to validate virtual screening models and then assayed 100 virtual hits (from 450,000 compounds) against UPPS from S. aureus and Escherichia coli. The most promising inhibitors (IC50 ∼2 μM, Ki ∼300 nM) had activity against MRSA, Listeria monocytogenes, Bacillus anthracis, and a vancomycin-resistant Enterococcus sp. with MIC or IC50 values in the 0.25-4 μg/mL range. Moreover, one compound (1), a rhodanine with close structural similarity to the commercial diabetes drug epalrestat, exhibited good activity as well as a fractional inhibitory concentration index (FICI) of 0.1 with methicillin against the community-acquired MRSA USA300 strain, indicating strong synergism.
Pharmacology Department, University of California San Diego , La Jolla, California 92093-0365, United States.
William
W
Sinko
Yang
Y
Wang
Wei
W
Zhu
Yonghui
Y
Zhang
Ferran
F
Feixas
Courtney L
CL
Cox
Douglas A
DA
Mitchell
Eric
E
Oldfield
J Andrew
JA
McCammon
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001463:Barbiturates / Q000494:pharmacology; D002473:Cell Wall / Q000187:drug effects; D016983:Enterococcus / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects; D020128:Inhibitory Concentration 50; D016106:Methicillin Resistance / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus; D062105:Molecular Docking Simulation; D012118:Resorcinols / Q000494:pharmacology; D012236:Rhodanine / Q000494:pharmacology; D054852:Small Molecule Libraries; D014166:Transferases / Q000037:antagonists & inhibitors; D020713:Vancomycin Resistance / Q000187:drug effects
D000900:Anti-Bacterial Agents; D001463:Barbiturates; D004791:Enzyme Inhibitors; D012118:Resorcinols; D054852:Small Molecule Libraries; D012236:Rhodanine; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C106821:cis-prenyl transferase; C023266:undecaprenyl pyrophosphate synthetase; C031389:resorcinol