Biofilms are collections of bacteria and bacterial-derived biomolecules that contribute to microbial antibiotic resistance. According to the Centers for Disease Control and Prevention, at least 2.8 million people are affected by antibiotic-resistant infections yearly with biofilms causing approximately 65% to 85% of all hospital related infections. Biofilm formation and dispersal is regulated, in part, by fatty acid analogs termed diffusible signal factors (DSF) although their mechanism(s) of action remain poorly understood. Dispersal of biofilms leads to increased bacterial susceptibility to antibiotics. The DSF, cis-2-decenoic acid (C2DA), has been shown to disperse biofilms in gram-positive and gram-negative bacteria along with preventing additional biofilm formation. The cis alkene conformation is integral to antibiofilm activity; however, it is also potentially susceptible to isomerization and oxidation due to heat, light, or oxidative conditions. We have previously synthesized a more potent C2DA analog- 2-heptylcyclopropane-1-carboxylic acid (2CP) which stabilizes the bioactive cis conformation through replacement of the alkene with a cis-like cyclopropyl group. As structural stability is vital to DSF activity, it is necessary to monitor and quantify the degradation of C2DA to either its trans isomer (T2DA) or other inactive oxidized products. Through the utilization of LC-ESI-MS, quantification of cis and trans decenoic acid isomers are possible. Short term stability of C2DA and 2CP has been analyzed through exposure to the photo-initiator Irgacure I2959. Long term stability is currently under investigation. A modular synthetic approach is being developed to create a library of 2CP analogs to examine the structure activity relationship (by varying head groups and alkyl chain length) and mechanism of action that define DSF-mediated antibiofilm actions.

Synthesis and quantitative analysis of diffusible signaling factor analogs as antibiofilm agents

ACS Fall 2021

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