Research

DSF was first identified in Xanthomonas campestris pv. Campestris (Xcc) and has been characterized as cis-11-methyl-dodecenoic acid (DSF, 3). In the attempt to identify the Structure Activity Relationship (SAR) of DSF molecules, Wang et al. synthesized derivatives of these fatty acids. Noticeably, the E-isomer of DSF, trans-11-methyl-dodecenoic acid (4), was 200 fold less active than that of the Z-isomer. Additionally, it was reported that the corresponding saturated fatty acid, 11-methyldodecanoic acid (5), is 20,000 fold less active. Therefore, the double bond at a, b position and its cis configuration are regarded as the structural motif of DSF molecules. In general, DSF derivatives that have the same carbon chain length as DSF exhibit higher activities than those with longer or shorter carbon chains. Furthermore, it is believed that the methyl group at the C-11 position also plays a certain role in the activity as the unbranched derivatives, cis-2-tridecenoic acid (6) and cis-2-dodecenoic acid (BDSF, 2) are 60-fold and 120-fold less active than DSF, respectively.

With the above preliminary information, we have targeted to synthesise molecules which mimic DSF and fit into the same biological receptors. However, due to subtle changes in their design, our molecules will instead switch off biofilm formation making the bacteria susceptible to antibiotics once again.

A library of sulfonamide derivatives of BDSF (BurkholderiaDiffusible Signal Factor)and DSF were synthesised and subsequently assayed.Encouragingly, several of these derivatives were discovered to successfully inhibit biofilm formation. Significantly, as the DSF signalling system is shared across different species of microbes, we are working with biologists across Europe and the US to test the activity of our compounds in several species which have been shown to be sensitive to DSF. Currently, we are working with biologists on P. aeruginosa (Prof Karin Sauer, Binghamton University, USA), S. maltophilia (Prof Isidre Gibert, Autonomous University of Barcelona, Spain), B. cenocepacia (Prof Leo Eberl, University of Zurich, Switzerland), C. albicans (Dr Dr. Slavena Vylkova, Hans Knoll Institute, Germany) and F. Novicida (Prof Monique Van Hoek, George Mason University, USA).