RESUMEN
Type II bacterial topoisomerases are well validated targets for antimicrobial chemotherapy. Novel bacterial type II topoisomerase inhibitors (NBTIs) of these targets are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. We now disclose the optimization of a class of NBTIs towards Gram-negative pathogens, especially against drug-resistant Pseudomonas aeruginosa. Physicochemical properties (pKa and logD) were optimized for activity against P. aeruginosa and for reduced inhibition of the hERG channel. The optimized analogs 9g and 9i displayed potent antibacterial activity against P. aeruginosa, and a significantly improved hERG profile over previously reported analogs. Compound 9g showed an improved QT profile in in vivo models and lower clearance in rat over earlier compounds. The compounds show promise for the development of new antimicrobial agents against drug-resistant Pseudomonas aeruginosa.
Asunto(s)
ADN-Topoisomerasas de Tipo II/metabolismo , Pseudomonas aeruginosa/efectos de los fármacos , Inhibidores de Topoisomerasa II/farmacología , Animales , Química Física , Perros , Relación Dosis-Respuesta a Droga , Farmacorresistencia Bacteriana/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Cobayas , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/enzimología , Pseudomonas aeruginosa/metabolismo , Ratas , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/químicaRESUMEN
Negamycin is a hydrophilic antimicrobial translation inhibitor that crosses the lipophilic inner membrane of Escherichia coli via at least two transport routes to reach its intracellular target. In a minimal salts medium, negamycin's peptidic nature allows illicit entry via a high-affinity route by hijacking the Dpp dipeptide transporter. Transport via a second, low-affinity route is energetically driven by the membrane potential, seemingly without the direct involvement of a transport protein. In mouse thigh models of E. coli infection, no evidence for Dpp-mediated transport of negamycin was found. The implication is that for the design of new negamycin-based analogs, the physicochemical properties required for cell entry via the low-affinity route need to be retained to achieve clinical success in the treatment of infectious diseases. Furthermore, clinical resistance to such analogs due to mutations affecting their ribosomal target or transport is expected to be rare and similar to that of aminoglycosides.