Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 1, Pages 123-128Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1219899110
Keywords
drug discovery; in silico high-throughput screening; peptidoglycan; protein structure
Categories
Funding
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
- Michigan Economic Development Corporation and Michigan Technology Tri-Corridor [085P1000817]
- US Public Health Services National Institutes of Health (NIH) [AI074233, GM65307, CA158191]
- Molecular Biophysics Training Grant [GM08326]
- NIH [GM31749, HD071600]
- National Science Foundation [MCB-1020765]
- National Biomedical Computation Resource
- Center for Theoretical Biological Physics
- Howard Hughes Medical Institute
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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) similar to 0.25 mu 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.
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