Giuseppe
Emeritus
[Source: Proceedings of the National Academy of the Sciences of the United States of America, full text: (LINK). Abstract, edited.]
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Antibacterial drug leads targeting isoprenoid biosynthesis
Wei Zhu<SUP>a</SUP>,<SUP>1</SUP>, Yonghui Zhang<SUP>b</SUP>,<SUP>1</SUP>,<SUP>2</SUP>, William Sinko<SUP>c</SUP>,<SUP>d</SUP>,<SUP>1</SUP>, Mary E. Hensler<SUP>e</SUP>, Joshua Olson<SUP>e</SUP>, Katie J. Molohon<SUP>f</SUP>, Steffen Lindert<SUP>c</SUP>, Rong Cao<SUP>a</SUP>, Kai Li<SUP>b</SUP>, Ke Wang<SUP>b</SUP>, Yang Wang<SUP>b</SUP>, Yi-Liang Liu<SUP>a</SUP>, Anna Sankovsky<SUP>b</SUP>, C?sar Augusto F. de Oliveira<SUP>c</SUP>,<SUP>g</SUP>, Douglas A. Mitchell<SUP>b</SUP>,<SUP>f</SUP>,<SUP>h</SUP>, Victor Nizet<SUP>e</SUP>, J. Andrew McCammon<SUP>c</SUP>,<SUP>d</SUP>,<SUP>g</SUP>,<SUP>i</SUP>,<SUP>2</SUP>, and Eric Oldfield<SUP>a</SUP>,<SUP>b</SUP>,<SUP>2</SUP>
<SUP></SUP>
Author Affiliations: <SUP>a</SUP>Center for Biophysics and Computational Biology and <SUP>b</SUP>Department of Chemistry, University of Illinois, Urbana, IL 61801; <SUP>c</SUP>Department of Pharmacology, <SUP>d</SUP>Biomedical Sciences Program, and <SUP>e</SUP>Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093; <SUP>f</SUP>Department of Microbiology, University of Illinois, Urbana, IL 61801; <SUP>g</SUP>Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093; <SUP>h</SUP>Institute for Genomic Biology, University of Illinois, Urbana, IL 61801; and <SUP>i</SUP>Howard 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)
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)<SUB>90</SUB> ∼0.25 ?g/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
Footnotes
<SUP>1</SUP>W.Z., Y.Z., and W.S. contributed equally to this work.
<SUP>2</SUP>To whom correspondence may be addressed. E-mail: eo@chad.scs.uiuc.edu, yhzhang@illinois.edu, or jmccammon@ucsd.edu.
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.
-Wei Zhu<SUP>a</SUP>,<SUP>1</SUP>, Yonghui Zhang<SUP>b</SUP>,<SUP>1</SUP>,<SUP>2</SUP>, William Sinko<SUP>c</SUP>,<SUP>d</SUP>,<SUP>1</SUP>, Mary E. Hensler<SUP>e</SUP>, Joshua Olson<SUP>e</SUP>, Katie J. Molohon<SUP>f</SUP>, Steffen Lindert<SUP>c</SUP>, Rong Cao<SUP>a</SUP>, Kai Li<SUP>b</SUP>, Ke Wang<SUP>b</SUP>, Yang Wang<SUP>b</SUP>, Yi-Liang Liu<SUP>a</SUP>, Anna Sankovsky<SUP>b</SUP>, C?sar Augusto F. de Oliveira<SUP>c</SUP>,<SUP>g</SUP>, Douglas A. Mitchell<SUP>b</SUP>,<SUP>f</SUP>,<SUP>h</SUP>, Victor Nizet<SUP>e</SUP>, J. Andrew McCammon<SUP>c</SUP>,<SUP>d</SUP>,<SUP>g</SUP>,<SUP>i</SUP>,<SUP>2</SUP>, and Eric Oldfield<SUP>a</SUP>,<SUP>b</SUP>,<SUP>2</SUP>
<SUP></SUP>
Author Affiliations: <SUP>a</SUP>Center for Biophysics and Computational Biology and <SUP>b</SUP>Department of Chemistry, University of Illinois, Urbana, IL 61801; <SUP>c</SUP>Department of Pharmacology, <SUP>d</SUP>Biomedical Sciences Program, and <SUP>e</SUP>Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093; <SUP>f</SUP>Department of Microbiology, University of Illinois, Urbana, IL 61801; <SUP>g</SUP>Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093; <SUP>h</SUP>Institute for Genomic Biology, University of Illinois, Urbana, IL 61801; and <SUP>i</SUP>Howard 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)
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)<SUB>90</SUB> ∼0.25 ?g/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
Footnotes
<SUP>1</SUP>W.Z., Y.Z., and W.S. contributed equally to this work.
<SUP>2</SUP>To whom correspondence may be addressed. E-mail: eo@chad.scs.uiuc.edu, yhzhang@illinois.edu, or jmccammon@ucsd.edu.
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.
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