Fungal biofilm inhibitors from a human oral microbiome-derived bacterium

The human mouth is home to a rich assortment of native and transient microorganisms. One of the commonly encountered bacterial species, Streptococcus mutans, was shown to generate the novel hybrid polyketide-nonribosomal peptide metabolite mutanobactin A (1). We have characterized three new analogues, mutanobactins B-D (2–4), and subjected these compounds to further biomedical evaluation. Metabolites 1, 2, and 4 were found to inhibit biofilm formation by the fungal oral-pathogen Candida albicans. Compound 4 was the most potent metabolite with an IC₅₀ value of 5.3 ± 0.9 μM. Using a combination of Marfey's analysis, proton spin–spin coupling, and ¹H-¹H NOESY data, we proposed absolute configuration assignments in toto for 1–3 and a partial assignment for 4. In addition, feeding studies with isotopically labeled precursor metabolites (acetate and amino acids) have helped to determine the biosynthetic origins of this unique natural product family.