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Fragment-based discovery of novel non-hydroxamate LpxC inhibitors with antibacterial activity
DOI:
10.1021/acs.jmedchem.0c01215
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)