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Science 8 November 1996:
Vol. 274. no. 5289, pp. 980 - 982
DOI: 10.1126/science.274.5289.980
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Reports

Antibacterial Agents That Inhibit Lipid A Biosynthesis

H. Russell Onishi, Barbara A. Pelak, Lynn S. Gerckens, Lynn L. Silver, Frederick M. Kahan, Meng-Hsin Chen, Arthur A. Patchett, Susan M. Galloway, Sheryl A. Hyland, Matt S. Anderson, Christian R. H. Raetz *

Lipid A constitutes the outer monolayer of the outer membrane of Gram-negative bacteria and is essential for bacterial growth. Synthetic antibacterials were identified that inhibit the second enzyme (a unique deacetylase) of lipid A biosynthesis. The inhibitors are chiral hydroxamic acids bearing certain hydrophobic aromatic moieties. They may bind to a metal in the active site of the deacetylase. The most potent analog (with an inhibition constant of about 50 nM) displayed a minimal inhibitory concentration of about 1 microgram per milliliter against Escherichia coli, caused three logs of bacterial killing in 4 hours, and cured mice infected with a lethal intraperitoneal dose of E. coli.

Departments of Microbiology, Medicinal Chemistry, and Biochemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
*   To whom correspondence should be addressed. Present address: Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.

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Science. ISSN 0036-8075 (print), 1095-9203 (online)