Peptide Analogs Isolated from Lactobacillus acidophilus Induce Multi-aggregate Formation and Impair Cell Division in Candida albicans

Abstract Yeasts of the Candida genus area major cause of infections regarding respiratory, digestive, and reproductive systems. Doderlin is an antimicrobial peptide isolated from Lactobacillus acidophilus and is notable for presenting a non-hemolytic effect. However, its long sequence and broad antimicrobial spectrum may limit its therapeutic applications. This study evaluated the antimicrobial activity, cytotoxicity, and morphofunctional effects of three Doderlin analogues (Dod H, Dod B, Dod T). Peptides were synthesized via Fmoc solid-phase synthesis. Antimicrobial activity and cellular effects were evaluated through growth assays, flow cytometry, and fluorescence and scanning electron microscopy. Among the analogues, Dod B exhibited the most promising antifungal activity, particularly against Candida albicans , while also inhibiting other clinically relevant Candida species, including Candida glabrata and Candida tropicalis . Notably, Dod B promoted the formation of interconnected cellular multi-aggregates and alterations in cellular physiology, potentially associated with interactions involving Seryl-tRNA synthetase (SerRS) and Peptidyl-prolyl isomerase ESS1. Although sequence optimization reduced the broad-spectrum activity observed for native Doderlin, it enhanced antifungal specificity and potency. These findings highlight Dod B as a promising therapeutic candidate for the treatment of Candida infections.