Fungal biofilm inhibitors from a human oral microbiome-derived bacterium

• Published in: Organic & biomolecular chemistry 2012-03, Vol.10 (10), p.2044-2050
• Main Authors: Wang, Xiaoru, Du, Lin, You, Jianlan, King, Jarrod B, Cichewicz, Robert H
• Format: Article
• Language: English
• Subjects: Antifungal Agents - chemistry; Antifungal Agents - isolation & purification; Antifungal Agents - metabolism; Antifungal Agents - pharmacology; Bacteria; Biofilms - drug effects; Candida albicans; Candida albicans - drug effects; Candidiasis - drug therapy; Fermentation; Humans; Metagenome; Models, Molecular; Mouth - microbiology; Peptides, Cyclic - chemistry; Peptides, Cyclic - isolation & purification; Peptides, Cyclic - metabolism; Peptides, Cyclic - pharmacology; Streptococcus mutans; Streptococcus mutans - metabolism
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c2ob06856g

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 IC(50) value of 5.3 ± 0.9 μM. Using a combination of Marfey's analysis, proton spin-spin coupling, and (1)H-(1)H 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.