ABSTRACT
The emergence and spread of multidrug-resistant (MDR) Gram negative bacteria presents a serious threat for public health. Novel antimicrobials that could overcome the resistance problems are urgently needed. UDP-3-O-(R-3-hydroxymyristol)-N-acetylglucosamine deacetylase (LpxC) is a cytosolic zinc-based deacetylase that catalyzes the first committed step in the biosynthesis of lipid A, which is essential for the survival of Gram-negative bacteria. Our efforts toward the discovery of novel LpxC inhibitors are presented herein.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/enzymology , Amidohydrolases/metabolism , Drug Discovery , Gram-Negative Bacterial Infections/drug therapy , Humans , Molecular Docking SimulationABSTRACT
Novel cyclic lipopeptides with different acyl tails were synthesized via a semisynthetic approach. Structure-activity relationship studies revealed that lipophilicity, chain length, and the location of key aromatic functionalities of the tail modulated activity. The lead compound surotomycin exhibited significantly improved in vitro activity compared with daptomycin (MIC90 0.5 vs 2 µg/mL) against Clostridium difficile including NAP1 epidemic strains. In hamster efficacy studies, surotomycin protected animals at a dose of 0.5 mg/kg, PO.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/therapeutic use , Clostridioides difficile/drug effects , Diarrhea/drug therapy , Enterocolitis, Pseudomembranous/drug therapy , Lipopeptides/chemistry , Lipopeptides/therapeutic use , Animals , Cricetinae , Diarrhea/microbiology , Enterocolitis, Pseudomembranous/complications , Male , Microbial Sensitivity Tests , Peptides, Cyclic/chemistry , Peptides, Cyclic/therapeutic use , Structure-Activity RelationshipABSTRACT
Daptomycin was shown to interact in vitro with pulmonary surfactant leading to reduction of its antibacterial activity. We report herein the preparation and anti-staphylococcal activity of a series of daptomycin analogs with reduced pulmonary surfactant interaction by replacing tryptophan with various amino acids.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Daptomycin/analogs & derivatives , Daptomycin/pharmacology , Pulmonary Surfactants/chemistry , Staphylococcus aureus/drug effects , Tryptophan/metabolism , Daptomycin/chemistry , Microbial Sensitivity Tests , Molecular ConformationABSTRACT
Oxazolidinone analogs bearing substituted piperidine or azetidine C-rings are described. Analogs with a methyl group at the 3-position of the azetidine ring or the 4-position of the piperidine ring exhibited reduced mitochondrial protein synthesis inhibition while retaining good antibacterial potency.
Subject(s)
Anti-Bacterial Agents/pharmacology , Mitochondria/metabolism , Oxazolidinones/pharmacology , Protein Biosynthesis/drug effects , Protein Synthesis Inhibitors/pharmacology , Anti-Bacterial Agents/chemistry , Enterococcus faecalis/drug effects , Microbial Sensitivity Tests , Oxazolidinones/chemistry , Protein Synthesis Inhibitors/chemistry , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effectsABSTRACT
Deoxynegamycin (1b) is a protein synthesis inhibitor with activity against Gram-negative (GN) bacteria. A series of conformationally restricted analogs were synthesized to probe its bioactive conformation. Indeed, some of the constrained analogs were found to be equal or better than deoxynegamycin in protein synthesis assay (1b, IC(50)=8.2 microM; 44, IC(50)=6.6 microM; 35e(2), IC(50)=1 microM). However, deoxynegamycin had the best in vitro whole cell antibacterial activity (Escherichia coli, MIC=4-16 microg/mL; Klebsiella pneumoniae, MIC=8 microg/mL) suggesting that other factors such as permeation may also be contributing to the overall whole cell activity. A new finding is that deoxynegamycin is efficacious in an E. coli murine septicemia model (ED(50)=4.8 mg/kg), providing further evidence of the favorable in vivo properties of this class of molecules.
