Mutanobactin D from the Human Microbiome: Chemistry, Biology and Molecular Dynamics Studies

ABSTRACT: Mutanobactin D is an interkingdom communicator derived from the human oral microbiome. The lipopeptide prevents yeast-to-hyphae morphogenesis in Candida albicans, notably without fungicidal or fungistatic activity. The mode of action and structure-activity relationship of mutanobactin D are unknown and prompt an interdisciplinary program of study. Stereoselective synthesis of designed mutanobactin D analogs reveals that the C26 configuration is crucial for bioactivity associated with inhibition of pathogenesis, or yeast-to-hyphae transition, in C. albicans. To shed light on this finding, we employ molecular dy-namics simulations of mutanobactin D and selected analogs in increasingly complex environments: Monophasic (water or CHCl3), interfacial (water/CHCl3), and explicit lipid membrane (phosphatidylcholine) models. Monophasic MD simulations do not distinguish between bioactive and inactive compounds. In contrast, at a polar/apolar interphase, a dominant, stable conformation emerges for mutanobactin D and bioactive analogs. Explicit lipid membrane simulations reinforce these results and further reveal the formation of a continuous, structured water cushion, which is not found for inactive analogs. Our studies collectively reveal how the stereodefined attachment of the lipid in the C26-C28 motif governs activity against C. albicans and provide a framework for understanding the membrane behavior of mutanobactin D, which may be coupled to its role in the human oral microbiome.