Crystal structure of LpxC from Pseudomonas aeruginosa complexed with the potent BB‐78485 inhibitor

Abstract

The cell wall in Gram-negative bacteria is surrounded by an outer membrane comprised of charged lipopolysaccharide (LPS) molecules that prevent entry of hydrophobic agents into the cell and protect the bacterium from many antibiotics. The hydrophobic anchor of LPS is lipid A, the biosynthesis of which is essential for bacterial growth and viability. UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is an essential zinc-dependant enzyme that catalyzes the conversion of UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine to UDP-3-O-(R-3-hydroxymyristoyl)glucosamine and acetate in the biosynthesis of lipid A, and for this reason, LpxC is an attractive target for antibacterial drug discovery. Here we disclose a 1.9 Å resolution crystal structure of LpxC from Pseudomonas aeruginosa (paLpxC) in a complex with the potent BB-78485 inhibitor. To our knowledge, this is the first crystal structure of LpxC with a small-molecule inhibitor that shows antibacterial activity against a wide range of Gram-negative pathogens. Accordingly, this structure can provide important information for lead optimization and rational design of the effective small-molecule LpxC inhibitors for successful treatment of Gram-negative infections.

Structural Basis of the Promiscuous Inhibitor Susceptibility of Escherichia coli LpxC

“…To test this hypothesis, we additionally determined the crystal structure of the EcLpxC/BB-78485 complex, which reveals an overall similar topology for LpxC and an identical binding mode of BB-78485 as the previously reported PaLpxC/BB-78485 structure, 21 with both naphthalene groups pointing toward the hydrophobic passage (Figure 4A). …”

Para-(benzoyl)-phenylalanine as a potential inhibitor against LpxC ofLeptospiraspp.: homology modeling, docking, and molecular dynamics study

“…Comparative structure modeling technique was implemented to predict tertiary structure of LpxC using Modeller 9v8 (Eswar, Eramian, Webb, Shen, & Sali, 2008). Crystal structure of LpxC in complex with inhibitor BB-78485 (PDB ID: 2VES) from Pseudomonas aeruginosa (Mochalkin et al, 2008) was choosen as structural template through BLASTP analysis (Altschul et al, 1997). CLUSTALX was used for initial target-template alignment (Thompson, Gibson, Plewniak, Jeanmougin, & Higgins, 1997).…”

“…Crystal structure of Leptospira LpxC is not available in the PDB database. However, availability of co-crystal structure of LpxC from Pseudomonas aeroginosa suggests a potent LpxC inhibitor, BB-78485 (Clements et al, 2002;Mochalkin, Knafels, & Lightle, 2008).…”

“…BB-78485 (Mochalkin et al, 2008) were used as control to propose potential LpxC inhibitors of Leptospira.…”

A new class of UDP-3-O-(R-3-hydroxymyristol)-N-acetylglucosamine deacetylase (LpxC) inhibitors for the treatment of Gram-negative infections: PCT application WO 2008027466

“…Unlike the previously reported LpxC inhibitors, 9 is a slow, tight-binding inhibitor of E. coli LpxC with a K i value of 2 nM that also demonstrates potent antibacterial activity against E. coli and P. aeruginosa [21]. Co-crystal structures of inhibitors 7 [22] and 9 [23] have recently been published, which can potentially aid in further improvements of inhibitors through structure-based design.…”