RESUMO
Antibiotics with new mechanisms of action are urgently required to combat the growing health threat posed by resistant pathogenic microorganisms. We synthesized a family of peptidomimetic antibiotics based on the antimicrobial peptide protegrin I. Several rounds of optimization gave a lead compound that was active in the nanomolar range against Gram-negative Pseudomonas spp., but was largely inactive against other Gram-negative and Gram-positive bacteria. Biochemical and genetic studies showed that the peptidomimetics had a non-membrane-lytic mechanism of action and identified a homolog of the beta-barrel protein LptD (Imp/OstA), which functions in outer-membrane biogenesis, as a cellular target. The peptidomimetic showed potent antimicrobial activity in a mouse septicemia infection model. Drug-resistant strains of Pseudomonas are a serious health problem, so this family of antibiotics may have important therapeutic applications.
Assuntos
Antibacterianos/farmacologia , Proteínas da Membrana Bacteriana Externa/metabolismo , Membrana Celular/metabolismo , Peptídeos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/metabolismo , Animais , Antibacterianos/síntese química , Antibacterianos/metabolismo , Peptídeos Catiônicos Antimicrobianos/química , Proteínas da Membrana Bacteriana Externa/química , Proteínas da Membrana Bacteriana Externa/genética , Desenho de Fármacos , Farmacorresistência Bacteriana/genética , Genes Bacterianos , Lipopolissacarídeos/metabolismo , Camundongos , Testes de Sensibilidade Microbiana , Mimetismo Molecular , Mutação , Biblioteca de Peptídeos , Peptídeos/síntese química , Peptídeos/química , Peptídeos/metabolismo , Estrutura Terciária de Proteína , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/ultraestrutura , Sepse/tratamento farmacológico , Sepse/microbiologiaRESUMO
The turn-forming D-Pro-L-Pro template has been frequently used to promote regular beta-hairpin conformations in cyclic protein epitope mimetics. Here the use of three isomeric biaryl templates has been studied as alternatives to D-Pro-L-Pro in the preparation of beta-hairpin peptidomimetics. The o,o'- o,m'- and m,m'-isomers of carboxymethyl- and aminomethyl-substituted biaryl templates have been incorporated into novel macrocyclic mimics of the naturally occurring cationic antimicrobial peptide protegrin I. The presence of the o-carboxymethyl-o'-aminomethyl-biaryl template within the macrocyclic peptide resulted in the appearance of slowly interconverting atropisomers. Although none of the resulting mimetics adopted stable beta-hairpin structures in aqueous solution, they all nevertheless retained a significant antimicrobial activity against Gram positive and Gram negative bacteria. These mimetics provide interesting starting points for an optimization program in the search for potent and novel antimicrobial compounds.
