RESUMEN
New antibiotics are urgently needed to address multidrug-resistant (MDR) bacteria. Herein we report that second-generation (G2) peptide dendrimers bearing a fatty acid chain at the dendrimer core efficiently kill Gram-negative bacteria including Pseudomonas aeruginosa and Acinetobacter baumannii, two of the most problematic MDR bacteria worldwide. Our most active dendrimer TNS18 is also active against Gram-positive methicillin-resistant Staphylococcus aureus. Based on circular dichroism and molecular dynamics studies, we hypothesize that TNS18 adopts a hydrophobically collapsed conformation in water with the fatty acid chain backfolded onto the peptide dendrimer branches and that the dendrimer unfolds in contact with the membrane to expose its lipid chain and hydrophobic residues, thereby facilitating membrane disruption leading to rapid bacterial cell death. Dendrimer TNS18 shows promising in vivo activity against MDR clinical isolates of A. baumannii and Escherichia coli, suggesting that lipidated peptide dendrimers might become a new class of antibacterial agents.
Asunto(s)
Antibacterianos/farmacología , Dendrímeros/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Lípidos/farmacología , Péptidos/farmacología , Acinetobacter baumannii/efectos de los fármacos , Animales , Antibacterianos/química , Dendrímeros/química , Relación Dosis-Respuesta a Droga , Escherichia coli/efectos de los fármacos , Lípidos/química , Ratones , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Péptidos/química , Pseudomonas aeruginosa/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The in vitro activity of the novel antimicrobial peptide dendrimer G3KL was evaluated against 32 Acinetobacter baumannii (including 10 OXA-23, 7 OXA-24, and 11 OXA-58 carbapenemase producers) and 35 Pseudomonas aeruginosa (including 18 VIM and 3 IMP carbapenemase producers) strains and compared to the activities of standard antibiotics. Overall, both species collections showed MIC50/90 values of 8/8 µg/ml and minimum bactericidal concentrations at which 50% or 90% of strains tested are killed (MBC50/90) of 8/8 µg/ml. G3KL is a promising molecule with antibacterial activity against multidrug-resistant and extensively drug-resistant A. baumannii and P. aeruginosa isolates.
Asunto(s)
Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos/farmacología , Dendrímeros/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Acinetobacter baumannii/enzimología , Acinetobacter baumannii/genética , Antibacterianos/síntesis química , Péptidos Catiónicos Antimicrobianos/síntesis química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Dendrímeros/síntesis química , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple/genética , Expresión Génica , Isoenzimas/genética , Isoenzimas/metabolismo , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pseudomonas aeruginosa/enzimología , Pseudomonas aeruginosa/genética , beta-Lactamasas/genética , beta-Lactamasas/metabolismo , beta-Lactamas/farmacologíaRESUMEN
Multidrug-resistant opportunistic bacteria, such as Pseudomonas aeruginosa, represent a major public health threat. Antimicrobial peptides (AMPs) and related peptidomimetic systems offer an attractive opportunity to control these pathogens. AMP dendrimers (AMPDs) with high activity against multidrug-resistant clinical isolates of P.â aeruginosa and Acinetobacterâ baumannii were now identified by a systematic survey of the peptide sequences within the branches of a distinct type of third-generation peptide dendrimers. Combined topology and peptide sequence design as illustrated here represents a new and general strategy to discover new antimicrobial agents to fight multidrug-resistant bacterial pathogens.
Asunto(s)
Péptidos Catiónicos Antimicrobianos/farmacología , Dendrímeros/farmacología , Descubrimiento de Drogas , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacos , Péptidos Catiónicos Antimicrobianos/síntesis química , Péptidos Catiónicos Antimicrobianos/química , Dendrímeros/síntesis química , Dendrímeros/química , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Relación Estructura-ActividadRESUMEN
Molecular dynamics simulations of the polycationic antimicrobial peptide dendrimer (Leu)8(DapLeu)4(DapPhe)2DapLys-NH2 binding to membranes suggest that electrostatic interactions with the polyanionic lipopolysaccharide (LPS) and conformational flexibility of the 2,3-diaminopropanoic acid (Dap) branching units drive its selective insertion into microbial membranes.