RESUMO
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.
Assuntos
Amidoidrolases/antagonistas & inibidores , Antibacterianos/química , Antibacterianos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/enzimologia , Amidoidrolases/metabolismo , Descoberta de Drogas , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Humanos , Simulação de Acoplamento MolecularRESUMO
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.
Assuntos
Antibacterianos/química , Antibacterianos/uso terapêutico , Clostridioides difficile/efeitos dos fármacos , Diarreia/tratamento farmacológico , Enterocolite Pseudomembranosa/tratamento farmacológico , Lipopeptídeos/química , Lipopeptídeos/uso terapêutico , Animais , Cricetinae , Diarreia/microbiologia , Enterocolite Pseudomembranosa/complicações , Masculino , Testes de Sensibilidade Microbiana , Peptídeos Cíclicos/química , Peptídeos Cíclicos/uso terapêutico , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Daptomicina/análogos & derivados , Daptomicina/farmacologia , Surfactantes Pulmonares/química , Staphylococcus aureus/efeitos dos fármacos , Triptofano/metabolismo , Daptomicina/química , Testes de Sensibilidade Microbiana , Conformação MolecularRESUMO
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.
Assuntos
Antibacterianos/farmacologia , Mitocôndrias/metabolismo , Oxazolidinonas/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , Inibidores da Síntese de Proteínas/farmacologia , Antibacterianos/química , Enterococcus faecalis/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Oxazolidinonas/química , Inibidores da Síntese de Proteínas/química , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacosRESUMO
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.