RESUMO
Despite major advances in the ß-lactamase inhibitor field, certain enzymes remain refractory to inhibition by agents recently introduced. Most important among these are the class B (metallo) enzyme NDM-1 of Enterobacteriaceae and the class D (OXA) enzymes of Acinetobacter baumannii. Continuing the boronic acid program that led to vaborbactam, efforts were directed toward expanding the spectrum to allow treatment of a wider range of organisms. Through key structural modifications of a bicyclic lead, stepwise gains in spectrum of inhibition were achieved, ultimately resulting in QPX7728 (35). This compound displays a remarkably broad spectrum of inhibition, including class B and class D enzymes, and is little affected by porin modifications and efflux. Compound 35 is a promising agent for use in combination with a ß-lactam antibiotic for the treatment of a wide range of multidrug resistant Gram-negative bacterial infections, by both intravenous and oral administration.
Assuntos
Ácidos Borínicos/farmacologia , Ácidos Borônicos/farmacologia , Ácidos Carboxílicos/farmacologia , Inibidores de beta-Lactamases/farmacologia , Animais , Bactérias/efeitos dos fármacos , Ácidos Borínicos/química , Ácidos Borínicos/farmacocinética , Ácidos Borínicos/uso terapêutico , Ácidos Borônicos/química , Ácidos Borônicos/farmacocinética , Ácidos Borônicos/uso terapêutico , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/uso terapêutico , Descoberta de Drogas , Infecções por Klebsiella/tratamento farmacológico , Camundongos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacocinética , Inibidores de beta-Lactamases/uso terapêuticoRESUMO
The discovery of a series of quinazolinone-based fungal efflux pump inhibitors by high-throughput screening for potentiation of fluconazole in C. albicans is described. Attempts to improve the aqueous solubility of screening hits led to the discovery of an analog with greatly improved physical properties and activity against clinically-relevant Candida spp.
Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antifúngicos/síntese química , Candida/efeitos dos fármacos , Proteínas Fúngicas/antagonistas & inibidores , Moduladores de Transporte de Membrana , Proteínas de Membrana Transportadoras/antagonistas & inibidores , Piperazinas/síntese química , Quinazolinas/síntese química , Antifúngicos/farmacologia , Candida/enzimologia , Farmacorresistência Fúngica , Sinergismo Farmacológico , Fluconazol/química , Fluconazol/farmacologia , Humanos , Técnicas In Vitro , Modelos Moleculares , Piperazinas/química , Piperazinas/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Solubilidade , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
To improve the aqueous solubility of anti-methicillin-resistant Staphylococcus aureus cephalosporin RWJ-333441 for parenteral administration, acyl derivatives of the C-3 primary amino group were prepared and evaluated for solubility, cleavage in serum in vitro, and conversion to RWJ-333441 in vivo. Improved solubility at physiologic pH values and release of RWJ-333441 in vitro and in vivo were observed for several prodrugs, including the aspartate derivative RWJ-333442.
Assuntos
Antibacterianos/farmacocinética , Cefalosporinas/farmacocinética , Lactamas , Pró-Fármacos/farmacocinética , Animais , Antibacterianos/sangue , Antibacterianos/química , Cefalosporinas/sangue , Cefalosporinas/química , Feminino , Humanos , Concentração de Íons de Hidrogênio , Infusões Intravenosas , Macaca mulatta , Masculino , Pró-Fármacos/administração & dosagem , Pró-Fármacos/síntese química , Ratos , Solubilidade , Água/químicaRESUMO
Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are among the most difficult to treat, Efforts toward the development of cephalosporin antimicrobial agents with activity against MRSA have been ongoing for the last decade. In spite of advancement of several potential drugs into clinical trials no such drugs are available for anti-MRSA therapy yet. The recent emergence of MRSA strains resistant to vancomycin, which is the treatment of choice for MRSA infection, has made the clinical need for new effective drugs even more pressing. In the present review structure-activity relationships are discussed with an emphasis on anti-MRSA activity, pharmacokinetics and efficacy in animal models. Clinical trial status of promising drug candidates is also provided where available.
