Details

Autor(en) / Beteiligte

• Barb, Adam W.
• Leavy, Tanya M.
• Robins, Lori I.
• Guan, Ziqiang
• Six, David A.
• Zhou, Pei
• Bertozzi, Carolyn R.
• Raetz, Christian R.H.

Titel

Uridine-based inhibitors as new leads for antibiotics targeting E. coli LpxC

Ist Teil von

• Biochemistry (Easton), 2009-04, Vol.48 (14), p.3068-3077

Erscheinungsjahr

2009

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• The UDP-3- O -( R -3-hydroxyacyl)- N -acetylglucosamine deacetylase LpxC catalyzes the committed reaction of lipid A (endotoxin) biosynthesis in Gram-negative bacteria and is a validated antibiotic target. Although several previously described compounds bind to the unique acyl chain binding passage of LpxC with high affinity, strategies to target the enzyme's UDP-binding site have not been reported. Here the identification of a series of uridine-based LpxC inhibitors is presented. The most potent examined, 1-68A, is a pH-dependent, two-step, covalent inhibitor of E. coli LpxC that competes with UDP to bind the enzyme in the first step of inhibition. Compound 1-68A exhibits a K I of 54 μM and a maximal rate of inactivation ( k inact ) of 1.7 min -1 at pH 7.4. Dithiothreitol, glutathione and the C207A mutant of E. coli LpxC prevent the formation of a covalent complex by 1-68A, suggesting a role for Cys-207 in inhibition. The inhibitory activity of 1-68A and a panel of synthetic analogs identified moieties necessary for inhibition. 1-68A and a 2-dehydroxy analog, 1-68Aa, inhibit several purified LpxC orthologs. These compounds may provide new scaffolds for extension of existing LpxC-inhibiting antibiotics to target the UDP binding pocket.