[Source: Proceedings of the National Academy of the Sciences of the United States of America, full text: (LINK). Abstract, edited.]
Antibacterial drug leads targeting isoprenoid biosynthesis
Wei Zhua,1, Yonghui Zhangb,1,2, William Sinkoc,d,1, Mary E. Henslere, Joshua Olsone, Katie J. Molohonf, Steffen Lindertc, Rong Caoa, Kai Lib, Ke Wangb, Yang Wangb, Yi-Liang Liua, Anna Sankovskyb, César Augusto F. de Oliveirac,g, Douglas A. Mitchellb,f,h, Victor Nizete, J. Andrew McCammonc,d,g,i,2, and Eric Oldfielda,b,2
Author Affiliations: aCenter for Biophysics and Computational Biology and bDepartment of Chemistry, University of Illinois, Urbana, IL 61801; cDepartment of Pharmacology, dBiomedical Sciences Program, and eDepartment of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093; fDepartment of Microbiology, University of Illinois, Urbana, IL 61801; gDepartment of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093; hInstitute for Genomic Biology, University of Illinois, Urbana, IL 61801; and iHoward Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093
Contributed by J. Andrew McCammon, November 16, 2012 (sent for review October 2, 2012)
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.
drug discovery - in silico high-throughput screening – peptidoglycan - protein structure
1W.Z., Y.Z., and W.S. contributed equally to this work.
Author contributions: W.Z., Y.Z., J.A.M., and E.O. designed research; W.Z., Y.Z., W.S., M.E.H., J.O., K.J.M., S.L., R.C., K.L., K.W., Y.W., Y.-L.L., A.S., C.A.F.d.O., D.A.M., V.N., J.A.M., and E.O. performed research; and E.O. wrote the paper.
The authors declare no conflict of interest.
Data deposition: Crystallography, atomic coordinates, and structure factors have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 3SGT, 3SGV, 3SGX, 3SH0, 4H2O, 4H38, 4H3C, 4H3A, 4H2J, 4H2M, and 4H8E).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1219899110/-/DCSupplemental.