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Antibacterial Drug Discovery Targeting the Lipopolysaccharide Biosynthetic Enzyme LpxC. Geneva: World Health Organization 2021.Įrwin AL. Global antimicrobial resistance and use surveillance system (GLASS) report 2021. Synthesis, structure, and SAR of Tetrahydropyran-based LpxC inhibitors. Murphy-Benenato KE, Olivier N, Choy A, Ross PL, Miller MD, Thresher J, et al. Enterococcus faecalis aggravates pyelonephritis caused by Pseudomonas aeruginosa in experimental ascending mixed urinary tract infection in mice. Tsuchimori N, Hayashi R, Shino A, Yamazaki T, Okonogi K. Breakpoint Tables for Interpretation of MICs and Zone Diameters. The European Committee on Antimicrobial Susceptibility Testing. Fragment-Based Discovery of Novel Non-Hydroxamate LpxC Inhibitors with Antibacterial Activity. Yamada Y, Takashima H, Walmsley DL, Ushiyama F, Matsuda Y, Kanazawa H, et al. Clinical and Laboratory Standards Institute, Wayne, PA. Performance standards for antimicrobial susceptibility testing informational supplement. 2021 30:115964.Ĭlinical and Laboratory Standards Institute. Lead optimization of 2-hydroxymethyl imidazoles as non-hydroxamate LpxC Inhibitors: Discovery of TP0586532. Ushiyama F, Takashima H, Matsuda Y, Ogata Y, Sasamoto N, Kurimoto-Tsuruta R, et al. N-Hydroxyformamide LpxC inhibitors, their in vivo efficacy in a mouse Escherichia coli infection model, and their safety in a rat hemodynamic assay. Why Hydroxamates May Not Be the Best Histone Deacetylase Inhibitors−What Some May Have Forgotten or Would Rather Forget? ChemMedChem 2016 11:15–21.įuruya T, Shapiro AB, Comita-Prevoir J, Kuenstner EJ, Zhang J, Ribe SD, et al. Hydroxamic acids as pharmacological agents. Muri EMF, Nieto MJ, Sindelar RD, Williamson JS. Design, synthesis, and properties of a potent inhibitor of Pseudomonas aeruginosa deacetylase LpxC. Piizzi G, Parker DT, Peng Y, Dobler M, Patnaik A, Wattanasin S, et al.
High susceptibility of MDR and XDR Gram-negative pathogens to biphenyl-diacetylene-based difluoromethyl-allo-threonyl-hydroxamate LpxC inhibitors. Titecat M, Liang X, Lee CJ, Charlet A, Hocquet D, Lambert T, et al. Optimization of LpxC inhibitors for antibacterial activity and cardiovascular safety. 2012, 3.Ĭohen F, Aggen JB, Andrews LD, Assar Z, Boggs J, Choi T, et al. Inhibition of LpxC protects mice from resistant Acinetobacter baumannii by modulating inflammation and enhancing phagocytosis. Lin L, Tan B, Pantapalangkoor P, Ho T, Baquir B, Tomaras A, et al. The first step of endotoxin biosynthesis is thermodynamically unfavorable. UDP-N-acetylglucosamine acyltransferase of Escherichia coli. (18)30278-X.Īnderson MS, Bull HG, Galloway SM, Kelly TM, Mohan S, Radika K, et al. Estimating the number of infections caused by antibiotic-resistant Escherichia coli and Klebsiella pneumoniae in 2014: a modelling study.
Temkin E, Fallach N, Almagor J, Gladstone BP, Tacconelli E, Carmeli Y. TP0586532 is predicted to exhibit a in vivo efficacy without cardiovascular toxicity and showed the potential of non-hydroxamate LpxC inhibitors as antibacterial agents against carbapenem-resistant Enterobacteriaceae. The estimated maximum unbound plasma concentration value at the effective dose of TP0586532 in murine infection models was around 13 μg ml −1. TP0586532 also showed an in vivo efficacy against murine systemic, urinary tract and lung infection models caused by meropenem- or ciprofloxacin-resistant strains. The MIC 90 of TP0586532 against clinical isolates of carbapenem-resistant Klebsiella pneumoniae was 4 μg ml −1. Herein, we report that TP0586532, a non-hydroxamate LpxC inhibitor, has a broad spectrum of antibacterial activity against carbapenem-resistant Enterobacteriaceae. The nonspecific inhibition of metalloenzymes through zinc ion chelation is one of possibilities leading to unwanted side effects.
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These LpxC inhibitors contain a hydroxamate moiety, which is a robust zinc ion chelator. Although a number of LpxC inhibitors have been identified, none have been approved as antibacterial agents. UDP-3- O-acyl- N-acetylglucosamine deacetylase (LpxC) is an attractive target for a new antibacterial agent. New antibiotics directed at previously unexplored targets are urgently needed to overcome resistance to existing antibiotic classes. The emergence of multi-drug resistant pathogenic bacteria, especially Gram-negative bacteria, is a worldwide health problem.