The Nobilamides: Potent Biofilm Inhibitors Produced by the Microbiota of Moon Snail Egg Masses

Bacterial biofilm infections have become increasingly challenging to treat as bacteria living in a biofilm state are more resistant to antibiotics and protected from the host immune response. Eradicating biofilm infections generally requires treatment with high doses of antibiotics for prolonged periods; however, the rise in antibiotic resistance further challenges these treatments. Unfortunately, there are no approved drugs that inhibit or disrupt biofilm formation. Here, we leveraged our library of bacteria associated with moon snails found in Puerto Rico, using mass spectrometry-based metabolomics, to discover biofilm inhibitors. Analysis of a chemical fraction library revealed a set of peptides in fractions exhibiting potent inhibition of Staphylococcus aureus biofilms. Bioassay-guided isolation led to the isolation of lipopeptides, the nobilamides, which were previously shown to possess antibacterial activity and TRPV1 antagonist properties but were never evaluated in a biofilm inhibition assay. A thorough evaluation of the biofilm inhibition activity of A-3302-B and A-3302-A revealed they potently inhibit biofilm formation with EC50 of 161 ± 85 and 598 ± 66 nM, respectively. Interestingly, nobilamide A and B, linear analogs, are 500-fold less active than their cyclic analogs.