Peptide analogs isolated from Bacillus acidophilus induce cell cycle arrest and multi-aggregate formation in Candida albicans

Yeasts of the Candida spp. are the main causes of infections in the respiratory, digestive and reproductive system. Doderlin is an antimicrobial peptide first isolated from Bacillus acidophilus , which shows no hemolysis, even at high concentrations. However, the sequence size and the broad spectrum are limitations to use as a drug. Therefore, the aim of this study was to evaluate the antimicrobial activity, cytotoxic potential and morphofunctional changes in microorganisms caused by analogues of Doderlin (Dod H, Dod B, Dod T). The molecules were synthesized using Fmoc solid-phase synthesis. Antimicrobial activity was tested in liquid cultures for 18, 24 and 48 hours. Flow cytometry was used to measure apoptosis, necrosis, cell cycle and mitochondrial potential. Finally, cell morphology and peptide internalization were analyzed using fluorescence and scanning electron microscopy. The Dod B analog showed the best antimicrobial activity, with an effect against C. albicans and other strains of the Candida genus, with MICs ranging from 125 − 64.5 µM. Furthermore, the peptide altered the yeast growth curve, arresting the cell cycle and reducing mitochondrial potential by inducing the formation of cellular multi-aggregates with interconnected membranes and cytoplasms. This multi-aggregation is potentially induced by interaction with the receptors Seryl-tRNA synthetase (SerRS) and Peptidyl-prolyl isomerase ESS1.Thus, the Dod B analog restricted its spectrum of action compared to the native sequence. In addition, its modification improved its biological activity, making it possible to identify its sequence as the active region of the peptide responsible for the anti-leaching activity.