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2.
Eur J Med Chem ; 221: 113488, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33991963

RESUMO

Naturally occurring cyclic antimicrobial peptides (AMPs) such as tyrocidine A (Tyrc A) and gramicidin S (GS) are appealing targets for the development of novel antibiotics. However, their therapeutic potentials are limited by undesired hemolytic activity and relatively poor activity against Gram-negative bacteria. Inspired by polycationic lipopeptide polymyxin B (PMB), the so called 'last-resort' antibiotic for the treatment of infections caused by multidrug-resistant Gram-negative bacteria, we synthesized and biologically evaluated a series of polycationic analogues derived from Tyrc A. We were able to obtain peptide 8 that possesses 5 positive charges exhibiting potent activities against both Gram-negative and Gram-positive bacteria along with totally diminished hemolytic activity. Intriguingly, antibacterial mechanism studies revealed that, rather than the 'pore forming' model that possessed by Tyrc A, peptide 8 likely diffuses membrane in a 'detergent-like' manner. Furthermore, when treating mice with peritonitis-sepsis, peptide 8 showed excellent antibacterial and anti-inflammatory activities in vivo.


Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Polimixina B/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Tirocidina/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Linhagem Celular , Relação Dose-Resposta a Droga , Farmacorresistência Bacteriana/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Polimixina B/química , Relação Estrutura-Atividade , Tirocidina/síntese química , Tirocidina/química
3.
ChemMedChem ; 16(2): 368-376, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33026182

RESUMO

Antimicrobial peptides (AMPs) are promising antibacterial agents often hindered by their undesired hemolytic activity. Inspired by gramicidin S (GS), a well-known cyclodecapeptide, we synthesized a panel of antibacterial cyclopeptidomimetics using ß,γ-diamino acids (ß,γ-DiAAs). We observed that peptidomimetic CP-2 displays a bactericidal activity similar to that of GS while possessing lower side-effects. Moreover, extensive studies revealed that CP-2 likely kills bacteria through membrane disruption. Altogether, CP-2 is a promising membrane-active antibiotic with therapeutic potential.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Gramicidina/farmacologia , Peptidomiméticos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Gramicidina/síntese química , Gramicidina/química , Potenciais da Membrana/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Conformação Molecular , Peptidomiméticos/síntese química , Peptidomiméticos/química , Relação Estrutura-Atividade
4.
ChemMedChem ; 15(12): 1089-1100, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32233075

RESUMO

Gramicidin S (GS), one of the most widely investigated antimicrobial peptides (AMPs), is known for its robust antimicrobial activity. However, it is restricted to topical application due to undesired hemolytic activity. With the aim of obtaining nontoxic GS analogues, we describe herein a molecular approach in which the native GS ß-turn region is replaced by synthetic ß,γ-diamino acids (ß,γ-DiAAs). Four ß,γ-DiAA diastereomers were employed to mimic the ß-turn structure to afford GS analogues GS3-6, which exhibit diminished hemolytic activity. A comparative structural study demonstrates that the (ßR,γS)-DiAA is the most-stable ß-turn mimic. To further improve the therapeutic index (e. g., high antibacterial activity and low hemolytic activity) and to extend the molecular diversity, GS5 and GS6 were used as structural scaffolds to introduce additional hydrophobic or hydrophilic groups. We show that GS6K, GS6F and GS display comparable antibacterial activity, and GS6K and GS6F have significantly decreased toxicity. Moreover, antibacterial mechanism studies suggest that GS6K kills bacteria mainly through the disruption of the membrane.


Assuntos
Antibacterianos/farmacologia , Gramicidina/análogos & derivados , Gramicidina/farmacologia , Antibacterianos/síntese química , Antibacterianos/toxicidade , Bactérias/efeitos dos fármacos , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Gramicidina/toxicidade , Hemólise/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Estereoisomerismo
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