Metallo-β-lactamases are bacterial zinc-dependent enzymes involved in the hydrolysis of β-lactamic antibiotics representing the main cause of bacterial resistance to carbapenems, drugs of last resort for treating in...Metallo-β-lactamases are bacterial zinc-dependent enzymes involved in the hydrolysis of β-lactamic antibiotics representing the main cause of bacterial resistance to carbapenems, drugs of last resort for treating infections caused by multiresistant bacteria. We elaborated the hypothesis that it is possible to inhibit the enzymatic activity of metallo-β-lactamases by lowering the availability of zinc in the extracellular medium using metal chelating agents such as EDTA carried on nanoparticles. Chitosan, as linear cationic polysaccharide is frequently used in biomedical and pharmaceutical applications, has been studied as a biocompatible encapsulating agent in drug delivery systems and is an ideal transport agent for bioactive molecular complexes in antibiotic applications due to its ability to associate with negatively charged substances. We developed novel nanoparticles using chitosan as a transport matrix for β-lactamic antibiotics. Nanoparticles were synthesized according to the ion gelation method using tripolyphosphate as crosslinking agent. Nanoparticles were functionalized by the adsorption of EDTA, which acts as complexifying agent for Zn2+ ions causing inhibition of metallo-β-lactamases activity. We evaluate the antimicrobial effects of EDTA-functionalized nanoparticles with an imipenem cargo on the clinical isolate P. aeruginosa AG1, a carbapenem-resistant high-risk clone ST-111 carrying both blaIMP-18 and blaVIM-2 metallo-β-lactamases genes.展开更多
Gram-negative bacilli Pseudomonas aeruginosa is an important pathogen in hospitalized patients, contributing to their morbidity and mortality due to its multiple resistance mechanisms. Therefore, as therapeutic option...Gram-negative bacilli Pseudomonas aeruginosa is an important pathogen in hospitalized patients, contributing to their morbidity and mortality due to its multiple resistance mechanisms. Therefore, as therapeutic options become restricted, the search for new agents is a priority. Latterly an accelerated increase in frequency of multidrug-resistant clinical strains has severely limited the availability of therapeutic options. Several in vitro and in vitro studies evaluating the efficacy of different antimicrobials agents and development of vaccines against P. aeruginosa have been reported as novel approaches, such as inhibition of virulence factor expression or inhibition of their metabolic pathways.展开更多
基金the Inter-University Fund for Higher Education(FEES)at the National Council of Rectors(CONARE)for financial support to this project through grant agreement No ACUERDO-VI-171-2014
文摘Metallo-β-lactamases are bacterial zinc-dependent enzymes involved in the hydrolysis of β-lactamic antibiotics representing the main cause of bacterial resistance to carbapenems, drugs of last resort for treating infections caused by multiresistant bacteria. We elaborated the hypothesis that it is possible to inhibit the enzymatic activity of metallo-β-lactamases by lowering the availability of zinc in the extracellular medium using metal chelating agents such as EDTA carried on nanoparticles. Chitosan, as linear cationic polysaccharide is frequently used in biomedical and pharmaceutical applications, has been studied as a biocompatible encapsulating agent in drug delivery systems and is an ideal transport agent for bioactive molecular complexes in antibiotic applications due to its ability to associate with negatively charged substances. We developed novel nanoparticles using chitosan as a transport matrix for β-lactamic antibiotics. Nanoparticles were synthesized according to the ion gelation method using tripolyphosphate as crosslinking agent. Nanoparticles were functionalized by the adsorption of EDTA, which acts as complexifying agent for Zn2+ ions causing inhibition of metallo-β-lactamases activity. We evaluate the antimicrobial effects of EDTA-functionalized nanoparticles with an imipenem cargo on the clinical isolate P. aeruginosa AG1, a carbapenem-resistant high-risk clone ST-111 carrying both blaIMP-18 and blaVIM-2 metallo-β-lactamases genes.
文摘Gram-negative bacilli Pseudomonas aeruginosa is an important pathogen in hospitalized patients, contributing to their morbidity and mortality due to its multiple resistance mechanisms. Therefore, as therapeutic options become restricted, the search for new agents is a priority. Latterly an accelerated increase in frequency of multidrug-resistant clinical strains has severely limited the availability of therapeutic options. Several in vitro and in vitro studies evaluating the efficacy of different antimicrobials agents and development of vaccines against P. aeruginosa have been reported as novel approaches, such as inhibition of virulence factor expression or inhibition of their metabolic pathways.
