Lua Silva¹, Francisco Eilton Sousa Lopes¹, Maria Laína Silva¹, Pedro Paulo Rodrigues Colares¹, Rossana de Aguiar Cordeiro¹

The increase in the occurrence of multidrug-resistant clinical isolates of Candida glabrata is associated, among other factors, with the fungus’s ability to stimulate the expression of the CDR1 protein—an ABC pleiotropic efflux transporter of multiple drugs—even when exposed to azole treatments, which are the main drugs used in fungal infections. This scenario calls for the development of new therapeutic strategies. This study aimed to identify, in osmotin-type plant protein sequences, potential antimicrobial peptides capable of inhibiting the CDR1 efflux pump of C. glabrata. For this purpose, online in silico tools were used, such as CAMPR3 for screening and PEP-FOLD3 for peptide modeling. Based on these analyses, two promising candidates were selected: OsmPep2 and OsmPep4. Both showed high antimicrobial probability, low toxicity, and favorable physicochemical properties. The three-dimensional structures of the peptides, after modeling and refinement, were docked with CDR1 models available from AlphaFold and Swiss-Model. Post-docking analyses showed that both peptides were able to form non-covalent interactions, salt bridges, and hydrogen bonds, both in the predicted active sites of the receptor and in the transmembrane region of the efflux pump. Thus, the formation of the complex, along with the number and quality of the interactions, suggests that osmotin-derived peptides can bind to and block the CDR1 protein in C. glabrata, representing a potential alternative to traditional therapies in the face of increasing fungal resistance.

Agradecimentos: Acknowledgments to CNPq and the Laboratory of Infectious Bioagents