A new bioinspired peptide on defensin from C. annuum fruits: Antimicrobial activity, mechanisms of action and therapeutical potential.

Background: Antimicrobial peptides, natural or synthetic, appear as promising molecules for antimicrobial therapy because of their both broad antimicrobial activity and mechanism of action. Herein, we determine the anti-Candida and antimycobacterial activities, mechanism of action on yeasts, and cytotoxicity on mammalian cells in the presence of the bioinspired peptide CaDef2.1.

Methods: CaDef2.1 was designed to attain the following criteria: high positive net charge; low molecular weight (<3000 Da); Boman index ≤2.5; and total hydrophobic ratio ≥ 40%. The mechanism of action was studied by growth inhibition, plasma membrane permeabilization, ROS induction, mitochondrial functionality, and metacaspase activity assays. The cytotoxicity on macrophages, monocytes, and erythrocytes were also determined.

Results: CaDef2.1 showed inhibitory activity against Candida spp. with MIC values ranging from 25 to 50 μM and the standard and clinical isolate of Mycobacterium tuberculosis with MIC of 33.2 and 55.4 μM, respectively. We demonstrate that CaDef2.1 is active against yeasts at different salt concentrations, induced morphological alterations, caused membrane permeabilization, increased ROS, causes loss of mitochondrial functionality, and activation of metacaspases. CaDef2.1 has low cytotoxicity against mammalian cells.

Conclusions: The results obtained showed that CaDef2.1 has great antimicrobial activity against Candida spp. and M. tuberculosis with low toxicity to host cells. For Candida spp., the treatment with CaDef2.1 induces a process of regulated cell death with apoptosis-like features.

General Significance: We show a new AMP bioinspired with physicochemical characteristics important for selectivity and antimicrobial activity, which is a promising candidate for drug development, mainly to control Candida infections.