Evaluation of Antifungal efficacy of three new cyclic lipopeptides of the class Bacillomycin from Bacillus subtilis RLID 12.1 [PublishAheadOfPrint]

New lipopeptide homologues (AF₃, AF₄ and AF₅) with antifungal activities against Candida and Cryptococcus spp. were purified from the cell free supernatant of Bacillus subtilis RLID 12.1. The lipopeptides AF₃, AF₄ and AF₅ were identified with the same peptide sequence Asn-Pro-Tyr-Asn-Gln-Thr-Ser with variations in the fatty acid branching type and chain length (anteiso-C₁₇, iso-C₁₇ and iso-C₁₈ respectively). Comparing the three homologues for minimum inhibitory concentrations (MIC) against 81 Candida (64 no.) and Cryptococcus (17 no.) clinical isolates and its cytotoxicity, AF₄ was found as the most promising antifungal lipopeptide which exhibited MIC_g of 3.31, 3.41, 3.48 and 2.83 μg/mL showing 100% inhibition against Candida albicans, Candida tropicalis, Candida auris and Cryptococcus neoformans respectively with low hemolysis value (<6%) and IC₅₀ values (13.31 μg/mL). The additive effects among the homologues AF₃, AF₄ and AF₅ were evaluated against 3 Candida species along with the cytotoxicity studies. Five combinations exhibited good additive interaction effects: AF₃, AF₄ (4, 4 μg/mL), AF₃, AF₅ (4, 4 μg/mL), AF₃, AF₅ (2, 4 μg/mL) AF₄, AF₅ (4, 4 μg/mL) and AF₄, AF₅ (2, 4 μg/mL) in planktonic cell inhibition and AF₃, AF₄ (4, 4 μg/mL), AF₃, AF₅ (4, 4 μg/mL) and AF₃, AF₅ (2, 4 μg/mL) in the inhibition of biofilm formation. However the combinations (AF₃, AF₄) and (AF₃, AF₅) showing >70% cell survival with low hemolysis (<5%) were found to be comparatively effective. To date this is the first study which describes the additive effects of lipopeptide homologues showing reduced cytotoxicity against mammalian cells and the combination might serve as a potent anti-biofilm forming substitute.

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