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

• Published in: Biochimica et biophysica acta. General subjects Vol. 1866; no. 11; p. 130218
• Main Authors: Taveira, Gabriel Bonan, de Oliveira Mello, Érica, Simão, Thatiana Lopes Biá Ventura, Cherene, Milena Bellei, de Oliveira Carvalho, André, Muzitano, Michelle Frazão, Lassounskaia, Elena, Pireda, Saulo, de Castro Miguel, Emílio, Basso, Luis Guilherme Mansor, Da Cunha, Maura, da Motta, Olney Vieira, Gomes, Valdirene Moreira
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.11.2022
• Subjects: Anti-Candida activity; Antimicrobial peptide; antimicrobial peptides; Antimycobacterial; Apoptosis-like; Candida; cell death; cytotoxicity; drug development; drug therapy; erythrocytes; growth retardation; hydrophobicity; macrophages; mammals; mechanism of action; membrane permeability; Membrane permeabilization; mitochondria; molecular weight; monocytes; Mycobacterium tuberculosis; plasma membrane; ROS increase; Apoptosis-like; Membrane permeabilization; Anti-Candida activity; ROS increase; Antimycobacterial; Antimicrobial peptide
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2022.130218

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 CaDef2.1G27-K44. CaDef2.1G27-K44 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. CaDef2.1G27-K44 showed inhibitory activity against Candida spp. with MIC100 values ranging from 25 to 50 μM and the standard and clinical isolate of Mycobacterium tuberculosis with MIC50 of 33.2 and 55.4 μM, respectively. We demonstrate that CaDef2.1G27-K44 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. CaDef2.1G27-K44 has low cytotoxicity against mammalian cells. The results obtained showed that CaDef2.1G27-K44 has great antimicrobial activity against Candida spp. and M. tuberculosis with low toxicity to host cells. For Candida spp., the treatment with CaDef2.1G27-K44 induces a process of regulated cell death with apoptosis-like features. 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. [Display omitted] •CaDef2.1G27-K44 is an antimimicrobial bioinspired peptide from the plant defensin CaDef2.1•CaDef2.1G27-K44 showed anti-Candida and antimycobacterial activity•CaDef2.1G27-K44 showed active against yeasts even at different salt concentrations•CaDef2.1G27-K44 induced cell membrane permeabilization, ROS, metacaspases, and mitochondrial functionality loss in yeasts;•CaDef2.1G27-K44 exhibited low hemolytic or cytotoxic properties for mammalian cells.