A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity

作者：Rab**** Francesc^*; Grau Campistany Ariadna; Vila Farres Xavier; Gonzalez Linares Javier; Borras Miquel; Vila Jordi; Manresa Angeles; Cajal Yolanda

来源：Scientific Reports, 2015, 5(1): 10558.

DOI：10.1038/srep10558

Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfidecontaining peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrugresistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain.

• 出版日期2015-5-29