RESUMO
The design, synthesis and structure-activity relationships of a series of oxazole-benzamide inhibitors of the essential bacterial cell division protein FtsZ are described. Compounds had potent anti-staphylococcal activity and inhibited the cytokinesis of the clinically-significant bacterial pathogen Staphylococcus aureus. Selected analogues possessing a 5-halo oxazole also inhibited a strain of S. aureus harbouring the glycine-to-alanine amino acid substitution at residue 196 of FtsZ which conferred resistance to previously reported inhibitors in the series. Substitutions to the pseudo-benzylic carbon of the scaffold improved the pharmacokinetic properties by increasing metabolic stability and provided a mechanism for creating pro-drugs. Combining multiple substitutions based on the findings reported in this study has provided small-molecule inhibitors of FtsZ with enhanced in vitro and in vivo antibacterial efficacy.
Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Benzamidas/farmacologia , Proteínas do Citoesqueleto/antagonistas & inibidores , Desenho de Fármacos , Oxazóis/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Benzamidas/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxazóis/química , Staphylococcus aureus/química , Relação Estrutura-AtividadeRESUMO
3-Methoxybenzamide (1) is a weak inhibitor of the essential bacterial cell division protein FtsZ. Alkyl derivatives of 1 are potent antistaphylococcal compounds with suboptimal drug-like properties. Exploration of the structure-activity relationships of analogues of these inhibitors led to the identification of potent antistaphylococcal compounds with improved pharmaceutical properties.
Assuntos
Antibacterianos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Proteínas do Citoesqueleto/antagonistas & inibidores , Piridinas/síntese química , Staphylococcus aureus/efeitos dos fármacos , Tiazóis/síntese química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Células CACO-2 , Divisão Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular , Hepatócitos/metabolismo , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Ligação Proteica , Piridinas/química , Piridinas/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/citologia , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologiaRESUMO
FtsZ is an essential bacterial guanosine triphosphatase and homolog of mammalian beta-tubulin that polymerizes and assembles into a ring to initiate cell division. We have created a class of small synthetic antibacterials, exemplified by PC190723, which inhibits FtsZ and prevents cell division. PC190723 has potent and selective in vitro bactericidal activity against staphylococci, including methicillin- and multi-drug-resistant Staphylococcus aureus. The putative inhibitor-binding site of PC190723 was mapped to a region of FtsZ that is analogous to the Taxol-binding site of tubulin. PC190723 was efficacious in an in vivo model of infection, curing mice infected with a lethal dose of S. aureus. The data validate FtsZ as a target for antibacterial intervention and identify PC190723 as suitable for optimization into a new anti-staphylococcal therapy.