title: Antibacterial drug leads targeting isoprenoid biosynthesis.
abstract: With the rise in resistance to antibiotics such as methicillin, there is a need for new drugs. We report here the discovery and X-ray crystallographic structures of 10 chemically diverse compounds (benzoic, diketo, and phosphonic acids, as well as a bisamidine and a bisamine) that inhibit bacterial undecaprenyl diphosphate synthase, an essential enzyme involved in cell wall biosynthesis. The inhibitors bind to one or more of the four undecaprenyl diphosphate synthase inhibitor binding sites identified previously, with the most active leads binding to site 4, outside the catalytic center. The most potent leads are active against Staphylococcus aureus [minimal inhibitory concentration (MIC)(90) ∼0.25 µg/mL], and one potently synergizes with methicillin (fractional inhibitory concentration index = 0.25) and is protective in a mouse infection model. These results provide numerous leads for antibacterial development and open up the possibility of restoring sensitivity to drugs such as methicillin, using combination therapies.
authors.affiliation: Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL 61801, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Zhang
authors.forename: William
authors.initials: W
authors.lastname: Sinko
authors.forename: Mary E
authors.initials: ME
authors.lastname: Hensler
authors.forename: Joshua
authors.initials: J
authors.lastname: Olson
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Molohon
authors.forename: Steffen
authors.initials: S
authors.lastname: Lindert
authors.forename: Rong
authors.initials: R
authors.lastname: Cao
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Yi-Liang
authors.initials: YL
authors.lastname: Liu
authors.forename: Anna
authors.initials: A
authors.lastname: Sankovsky
authors.forename: César Augusto F
authors.initials: CA
authors.lastname: de Oliveira
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Mitchell
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001565:Benzoates; D053898:Biosynthetic Pathways / Q000187:drug effects*; D002473:Cell Wall / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004164:Diphosphonates; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D008712:Methicillin / Q000378:metabolism; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011760:Pyrrolidinones; D013211:Staphylococcus aureus / Q000187:drug effects*; D013729:Terpenes / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D001565:Benzoates; D004164:Diphosphonates; D011760:Pyrrolidinones; D013729:Terpenes; C009435:tetramic acid; D019883:Alkyl and Aryl Transferases; C023266:undecaprenyl pyrophosphate synthetase; D008712:Methicillin