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Insights into the Zinc-Dependent Deacetylase LpxC: Biochemical Properties and Inhibitor Design

[ Vol. 16 , Issue. 21 ]

Author(s):

Dmitrii V. Kalinin and Ralph Holl   Pages 2379 - 2430 ( 52 )

Abstract:


The bacterial enzyme UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC), catalyzing the first committed step of lipid A biosynthesis, represents a promising target in the development of novel antibiotics against Gram-negative bacteria. Structure, catalytic reaction mechanism and regulation of the Zn2+-dependent metalloamidase have been intensively investigated. The enzyme is required for growth and viability of Gram-negative bacteria, displays no sequence homology with any mammalian protein, but is highly conserved in Gram-negative bacteria, thus permitting the development of Gram-negative selective antibacterial agents with limited off-target effects. Several smallmolecule LpxC inhibitors have been developed, like the substrate analog TU-514 (12a), the aryloxazoline L-161,240 (13w), the sulfonamide BB-78485 (23a), the N-aroyl-L-threonine derivative CHIR-090 (24a), the sulfone-containing pyridone LpxC-3 (43e), and the uridine-based inhibitor 1-68A (47a), displaying diverse inhibitory and antibacterial activities. Most of these compounds share a Zn2+-binding hydroxamate moiety attached to a structural element addressing the hydrophobic tunnel or the UDP binding site. The butadiynyl derivative ACHN-975 (28) is the first LpxC inhibitor entering clinical trials.

Keywords:

LpxC, lipid A, Antibiotics, LpxC inhibitors, Structure-activity relationships.

Affiliation:

Institut für Pharmazeutische und Medizinische Chemie der Westfalischen Wilhelms-Universitat Munster, Corrensstr. 48, D-48149 Münster, Germany.



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