Mechanism and inhibition of LpxC: an essential zinc-dependent deacetylase of bacterial lipid A synthesis.
Multi-drug resistant (MDR), pathogenic Gram-negative bacteria pose a serious health threat, and novel antibiotic targets must be identified to combat MDR infections. One promising target is the zinc-dependent metalloamidase UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC), which catalyzes the committed step of lipid A (endotoxin) biosynthesis. LpxC is an essential, single copy gene that is conserved in virtually all Gram-negative bacteria. LpxC structures, revealed by NMR and X-ray crystallography, demonstrate that LpxC adopts a novel 'beta-alpha-alpha-beta sandwich' fold and encapsulates the acyl chain of the substrate with a unique hydrophobic passage. Kinetic analysis revealed that LpxC functions by a general acid-base mechanism, with a glutamate serving as the general base. Many potent LpxC inhibitors have been identified, and most contain a hydroxamate group targeting the catalytic zinc ion. Although early LpxC-inhibitors were either narrow-spectrum antibiotics or broad-spectrum in vitro LpxC inhibitors with limited antibiotic properties, the recently discovered compound CHIR-090 is a powerful antibiotic that controls the growth of Escherichia coli and Pseudomonas aeruginosa, with an efficacy rivaling that of the FDA-approved antibiotic ciprofloxacin. CHIR-090 inhibits a wide range of LpxC enzymes with sub-nanomolar affinity in vitro, and is a two-step, slow, tight-binding inhibitor of Aquifex aeolicus and E. coli LpxC. The success of CHIR-090 suggests that potent LpxC-targeting antibiotics may be developed to control a broad range of Gram-negative bacteria.
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Adam W
AW
Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, 27710, USA.
Zhou
Pei
P
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D000818:Animals; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008050:Lipid A / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013912:Threonine / Q000031:analogs & derivatives / Q000494:pharmacology; D015032:Zinc / Q000037:antagonists & inhibitors / Q000378:metabolism*
C525369:CHIR 090; D029968:Escherichia coli Proteins; D006877:Hydroxamic Acids; D008050:Lipid A; D013912:Threonine; D000581:Amidohydrolases; C097307:UDP-3-O-acyl-N-acetylglucosamine deacetylase; D015032:Zinc