he Antimicrobial Peptide MK58911-NH2 Acts on Planktonic, Biofilm, and Intramacrophage Cells of Cryptococcus neoforman

Author(s)

Singulani, Junya de Lacorte ^[1] ; Oliveira, Lariane Teodoro ^[1] ; Ramos, Marina Dorisse ^[1] ; Fregonezi, Nathalia Ferreira ^[1] ; Gomes, Paulo Cesar ^[1] ; Galeane, Mariana Cristina ^[1] ; Palma, Mario Sergio ^[2] ; Fusco Almeida, Ana Marisa ^[1] ; Soares Mendes Giannini, Maria Jose ^[1]

Affiliation

^[1] Sao Paulo State Univ, UNESP, Sch Pharmaceut Sci, Dept Clin Anal, Araraquara, SP - Brazil

^[2] Sao Paulo State Univ, UNESP, Inst Biosci, Dept Basic & Appl Biol, Rio Claro - Brazil

• Document type: Journal article
• Source: Antimicrobial Agents and Chemotherapy; v. 65, n. 12 NOV 2021.
• Web of Science Citations: 1

Abstract

Cryptococcosis is associated with high rates of morbidity and mortality, especially in AIDS patients. Its treatment is carried out by combining amphotericin B and azoles or flucytosine, which causes unavoidable toxicity issues in the host. Thus, the urgency in obtaining new antifungals drives the search for antimicrobial peptides (AMPs). This study aimed to extend the understanding of the mechanism of action of an AMP analog from wasp peptide toxins, MK58911-NH2, on Cryptococcus neoformans. We also evaluated if MK58911-NH2 can act on cryptococcal cells in macrophages, biofilms, and an immersion zebrafish model of infection. Finally, we investigated the structure-antifungal action and the toxicity relationship of MK58911-NH2 fragments and a derivative of this peptide (MH58911-NH2). The results demonstrated that MK58911-NH2 did not alter the fluorescence intensity of the cell wall-binding dye calcofluor white or the capsule-binding dye 18b7 antibody-fluorescein isothiocyanate (FITC) in C. neoformans but rather reduced the number and size of fungal cells. This activity reduced the fungal burden of C. neoformans in both macrophages and zebrafish embryos as well as within biofilms. Three fragments of the MK58911-NH2 peptide showed no activity against Cryptococcus and not toxicity in lung cells. The derivative peptide MH58911-NH2, in which the lysine residues of MK58911-NH2 were replaced by histidines, reduced the activity against extracellular and intracellular C. neoformans. On the other hand, it was active against biofilms and showed reduced toxicity. In summary, these results showed that peptide MK58911-NH2 could be a promising agent against cryptococcosis. This work also opens a perspective for the verification of the antifungal activity of other derivatives. (AU)

• FAPESP's process: 16/16212-5 - Natural proteopeptides from the Brazilian fauna, flora and microbiota as potential models for the rational development of new drugs of therapeutic use: isolation, structure elucidation, chemical synthesis and functional activity assays
• Grantee: Mario Sergio Palma
• Support Opportunities: BIOTA-FAPESP Program - Thematic Grants
• FAPESP's process: 17/06658-9 - Platform for antifungal development in a nanostructured lipid system aiming at efficacy and safety in alternative animal models
• Grantee: Junya de Lacorte Singulani
• Support Opportunities: Scholarships in Brazil - Post-Doctoral