Biofilms which form during infection provide a barrier to immune surveillance and limit antibiotic access to bacteria within the biofilm. Quorum sensing is an early event in biofilm formation where bacteria synthesize and release autoinducers to effect the communication necessary for biofilm development. Blockade of quorum sensing is an attractive therapeutic prospect given that this is not a bactericidal strategy, as only cellular communication is disrupted, thus lessening selective pressure. Additionally, co-administration of quorum sensing inhibitors with antibiotics may render bacteria more susceptible to the latter, given that biofilm formation has been disrupted.

Previous research has indicated that blockade of the enzyme methylthioadenosine nucleosidase (MTAN) can control levels of key quorum sensing molecules, autoinducers 1 and 2. We have developed transition state analog inhibitors that display remarkably high affinity to MTAN enzymes from a variety of bacteria including S. pneumoniae, E. coli, H. pylori, N. meningitidis, and S. aureus. Here, we screened a panel of MTAN inhibitors in dose-response experiments against a clinical isolate of S. epidermidis, measuring their impact on both growth and biofilm formation. S. epidermidis was selected given its prevalence in clinically relevant biofilm-related infections. Of the inhibitors screened, we report an 80% reduction in biofilm formation at 1 µM of the MTAN inhibitor Methylthio-DADMe-Immucillin A, with no impact on cell growth. A second candidate, n-Butyl-DADMe-Immucillin A, showed a 95% reduction in biofilm formation at a concentration of 10 µM. These positive data indicate that specific MTAN inhibitors may provide a new approach to treating infections that require bacterial biofilm formation.