7cib

Crystal structure of P.aeruginosa LpxC in complex with inhibitorCrystal structure of P.aeruginosa LpxC in complex with inhibitor

Structural highlights

7cib is a 1 chain structure with sequence from Pseudomonas aeruginosa PAO1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.61Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LPXC_PSEAE Involved in the biosynthesis of lipid A, a phosphorylated glycolipid that anchors the lipopolysaccharide to the outer membrane of the cell.

Publication Abstract from PubMed

UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a zinc metalloenzyme that catalyzes the first committed step in the biosynthesis of Lipid A, an essential component of the cell envelope of Gram-negative bacteria. The most advanced, disclosed LpxC inhibitors showing antibacterial activity coordinate zinc through a hydroxamate moiety with concerns about binding to other metalloenzymes. Here, we describe the discovery, optimization, and efficacy of two series of compounds derived from fragments with differing modes of zinc chelation. A series was evolved from a fragment where a glycine moiety complexes zinc, which achieved low nanomolar potency in an enzyme functional assay but poor antibacterial activity on cell cultures. A second series was based on a fragment that chelated zinc through an imidazole moiety. Structure-guided design led to a 2-(1S-hydroxyethyl)-imidazole derivative exhibiting low nanomolar inhibition of LpxC and a minimum inhibitory concentration (MIC) of 4 mug/mL against Pseudomonas aeruginosa, which is little affected by the presence of albumin.

Fragment-Based Discovery of Novel Non-Hydroxamate LpxC Inhibitors with Antibacterial Activity.,Yamada Y, Takashima H, Walmsley DL, Ushiyama F, Matsuda Y, Kanazawa H, Yamaguchi-Sasaki T, Tanaka-Yamamoto N, Yamagishi J, Kurimoto-Tsuruta R, Ogata Y, Ohtake N, Angove H, Baker L, Harris R, Macias A, Robertson A, Surgenor A, Watanabe H, Nakano K, Mima M, Iwamoto K, Okada A, Takata I, Hitaka K, Tanaka A, Fujita K, Sugiyama H, Hubbard RE J Med Chem. 2020 Nov 19. doi: 10.1021/acs.jmedchem.0c01215. PMID:33210531^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Yamada Y, Takashima H, Walmsley DL, Ushiyama F, Matsuda Y, Kanazawa H, Yamaguchi-Sasaki T, Tanaka-Yamamoto N, Yamagishi J, Kurimoto-Tsuruta R, Ogata Y, Ohtake N, Angove H, Baker L, Harris R, Macias A, Robertson A, Surgenor A, Watanabe H, Nakano K, Mima M, Iwamoto K, Okada A, Takata I, Hitaka K, Tanaka A, Fujita K, Sugiyama H, Hubbard RE. Fragment-Based Discovery of Novel Non-Hydroxamate LpxC Inhibitors with Antibacterial Activity. J Med Chem. 2020 Nov 19. doi: 10.1021/acs.jmedchem.0c01215. PMID:33210531 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c01215

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OCA

[1] Yamada Y, Takashima H, Walmsley DL, Ushiyama F, Matsuda Y, Kanazawa H, Yamaguchi-Sasaki T, Tanaka-Yamamoto N, Yamagishi J, Kurimoto-Tsuruta R, Ogata Y, Ohtake N, Angove H, Baker L, Harris R, Macias A, Robertson A, Surgenor A, Watanabe H, Nakano K, Mima M, Iwamoto K, Okada A, Takata I, Hitaka K, Tanaka A, Fujita K, Sugiyama H, Hubbard RE. Fragment-Based Discovery of Novel Non-Hydroxamate LpxC Inhibitors with Antibacterial Activity. J Med Chem. 2020 Nov 19. doi: 10.1021/acs.jmedchem.0c01215. PMID:33210531 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c01215

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