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Fragment-based discovery of novel non-hydroxamate LpxC inhibitors with antibacterial activity

DOI: 10.1021/acs.jmedchem.0c01215 DOI Help

Authors: Yousuke Yamada (Taisho Pharmaceutical Co., Ltd) , Hajime Takashima (Taisho Pharmaceutical Co., Ltd) , David Lee Walmsley (Vernalis (R&D) Ltd) , Fumihito Ushiyama (Taisho Pharmaceutical Co., Ltd) , Yohei Matsuda (Taisho Pharmaceutical Co., Ltd) , Harumi Kanazawa (Taisho Pharmaceutical Co., Ltd) , Toru Yamaguchi-Sasaki (Taisho Pharmaceutical Co., Ltd) , Nozomi Tanaka-Yamamoto (Taisho Pharmaceutical Co., Ltd) , Junya Yamagishi (Taisho Pharmaceutical Co., Ltd) , Risa Kurimoto-Tsuruta (Taisho Pharmaceutical Co., Ltd) , Yuya Ogata (Taisho Pharmaceutical Co., Ltd) , Norikazu Ohtake (Taisho Pharmaceutical Co., Ltd) , Hayley Angove (Vernalis (R&D) Ltd) , Lisa Baker (Vernalis (R&D) Ltd) , Richard Harris (Vernalis (R&D) Ltd) , Alba Macias (Vernalis (R&D) Ltd) , Alan Robertson (Vernalis (R&D) Ltd) , Allan Surgenor (Vernalis (R&D) Ltd) , Hayato Watanabe (Taisho Pharmaceutical Co., Ltd) , Koichiro Nakano (Taisho Pharmaceutical Co., Ltd) , Masashi Mima (Taisho Pharmaceutical Co., Ltd) , Kunihiko Iwamoto (Taisho Pharmaceutical Co., Ltd) , Atsushi Okada (Taisho Pharmaceutical Co., Ltd) , Iichiro Takata (Taisho Pharmaceutical Co., Ltd) , Kosuke Hitaka (Taisho Pharmaceutical Co., Ltd) , Akihiro Tanaka (Taisho Pharmaceutical Co., Ltd) , Kiyoko Fujita (Taisho Pharmaceutical Co., Ltd) , Hiroyuki Sugiyama (Taisho Pharmaceutical Co., Ltd) , Roderick E. Hubbard (Vernalis (R&D) Ltd)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: November 2020
Diamond Proposal Number(s): 12428

Abstract: 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 μg/mL against Pseudomonas aeruginosa, which is little affected by the presence of albumin.

Journal Keywords: Zinc; Peptides and proteins; Crystal structure; Inhibitors; Imidazoles

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography

Other Facilities: Soleil Synchrotron

Added On: 23/11/2020 10:10

Discipline Tags:

Pathogens Antibiotic Resistance Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)