ABSTRACT
In this paper, we present some elements of our optimization program to decouple triclosan's specific FabI effect from its nonspecific cytotoxic component. The implementation of this strategy delivered highly specific, potent, and nonbiocidal new FabI inhibitors. We also disclose some preclinical data of one of their representatives, 83, a novel antibacterial compound active against resistant staphylococci and some clinically relevant Gram negative bacteria that is currently undergoing clinical trials.
Subject(s)
Anti-Infective Agents, Local/pharmacology , Benzamides/pharmacology , Drug Resistance, Multiple, Bacterial/drug effects , Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/antagonists & inhibitors , Gram-Negative Bacteria/drug effects , Phenyl Ethers/pharmacology , Triclosan/pharmacology , Animals , Anti-Infective Agents, Local/chemical synthesis , Benzamides/chemical synthesis , Cells, Cultured , Dogs , Drug Evaluation, Preclinical , Humans , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Phenyl Ethers/chemical synthesis , Rats , Structure-Activity Relationship , Triclosan/chemical synthesisABSTRACT
Extraintestinal pathogenic Escherichia coli (ExPEC) strains cause a large spectrum of infections. The majority of ExPEC strains are closely related to the B2 or the D phylogenetic group. The aim of our study was to develop a protein-based vaccine against these ExPEC strains. To this end, we identified ExPEC-specific genomic regions, using a comparative genome analysis, between the nonpathogenic E. coli strain K-12 MG1655 and ExPEC strains C5 (meningitis isolate) and CFT073 (urinary tract infection isolate). The analysis of these genomic regions allowed the selection of 40 open reading frames, which are conserved among B2/D clinical isolates and encode proteins with putative outer membrane localization. These genes were cloned, and recombinant proteins were purified and assessed as vaccine candidates. After immunization of BALB/c mice, five proteins induced a significant protective immunity against a lethal challenge with a clinical E. coli strain of the B2 group. In passive immunization assays, antigen-specific antibodies afforded protection to naive mice against a lethal challenge. Three of these antigens were related to iron acquisition metabolism, an important virulence factor of the ExPEC, and two corresponded to new, uncharacterized proteins. Due to the large number of genetic differences that exists between commensal and pathogenic strains of E. coli, our results demonstrate that it is possible to identify targets that elicit protective immune responses specific to those strains. The five protective antigens could constitute the basis for a preventive subunit vaccine against diseases caused by ExPEC strains.