RESUMEN
IMP-1 metallo-beta-lactamase (class B) is a plasmid-borne zinc metalloenzyme that efficiently hydrolyzes beta-lactam antibiotics, including carbapenems, rendering them ineffective. Because IMP-1 has been found in several clinically important carbapenem-resistant pathogens, there is a need for inhibitors of this enzyme that could protect broad spectrum antibiotics such as imipenem from hydrolysis and thus extend their utility. We have identified a series of 2,3-(S,S)-disubstituted succinic acids that are potent inhibitors of IMP-1. Determination of high resolution crystal structures and molecular modeling of succinic acid inhibitor complexes with IMP-1 has allowed an understanding of the potency, stereochemistry, and structure-activity relationships of these inhibitors.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Plásmidos , Succinatos/farmacología , beta-Lactamasas/metabolismo , Cristalografía por Rayos X , Cinética , Modelos Moleculares , Estructura Molecular , beta-Lactamasas/químicaRESUMEN
The synthesis and biological evaluation of a series of dicationic-substituted 2-fluorenonylcarbapenems is described. This class of compounds showed enhanced water solubility while maintaining potent activity against MRS. Introduction of a 1-beta-methyl substituent was found to improve pharmacokinetics.
Asunto(s)
Carbapenémicos/farmacología , Staphylococcus aureus/efectos de los fármacos , Animales , Carbapenémicos/farmacocinética , Carbapenémicos/uso terapéutico , Cationes , Semivida , Macaca mulatta , Resistencia a la Meticilina , Ratones , Pruebas de Sensibilidad Microbiana , Solubilidad , Infecciones Estafilocócicas/tratamiento farmacológicoRESUMEN
A series of amidinium-substituted 2-dibenzofuranylcarbapenems with potent activity against MRSA has been synthesized via a Stille cross-coupling reaction. These new carbapenems show reduced serum protein binding and improved in vivo efficacy as a consequence of the positively charged amidinium substituent.
Asunto(s)
Amidinas/química , Carbapenémicos/síntesis química , Carbapenémicos/farmacología , Staphylococcus aureus/efectos de los fármacos , Carbapenémicos/química , Resistencia a la Meticilina , Pruebas de Sensibilidad MicrobianaRESUMEN
A regioisomeric set of 2-naphthylcarbapenems featuring cationic substituents was synthesized. Optimal placement of the cationic group was found to markedly improve activity against methicillin-resistant staphylococci while maintaining a good spectrum of gram-negative activity.
Asunto(s)
Antibacterianos/síntesis química , Carbapenémicos/síntesis química , Resistencia a la Meticilina , Naftalenos/síntesis química , Staphylococcus/efectos de los fármacos , Antibacterianos/farmacología , Carbapenémicos/farmacología , Dipeptidasas/metabolismo , Estructura Molecular , Naftalenos/farmacologíaRESUMEN
IMP-1 metallo-beta-lactamase is a transferable carbapenem-hydrolyzing enzyme found in some clinical isolates of Pseudomonas aeruginosa, Serratia marcescens and Klebsiella pneumoniae. Bacteria that express IMP-1 show significantly reduced sensitivity to carbapenems and other beta-lactam antibiotics. A series of thioester derivatives has been shown to competitively inhibit purified IMP-1. As substrates for IMP-1, the thioesters yielded thiol hydrolysis products which themselves were reversible competitive inhibitors. The thioesters also increased sensitivity to the carbapenem L-742,728 in an IMP-1-producing laboratory stain of Escherichia coli, but will need further modification to improve their activity in less permeable organisms such as Pseudomonas and Serratia. Nonetheless, the thioester IMP-1 inhibitors offer an encouraging start to overcoming metallo-beta-lactamase-mediated resistance in bacteria.
Asunto(s)
Bacterias/efectos de los fármacos , Carbapenémicos/metabolismo , Inhibidores Enzimáticos/farmacología , Compuestos de Sulfhidrilo/farmacología , Inhibidores de beta-Lactamasas , Bacterias/enzimologíaRESUMEN
Potent thioester and thiol inhibitors of IMP-1 metallo-beta-lactamase have been synthesized employing a solid-phase Mitsunobu reaction as the key step.