Fighting Burkholderia cenocepacia: new drugs, new targets and efflux transporters

Burkholderia cenocepacia J315 is an opportunistic pathogen for cystic fibrosis patients particularly dangerous because of its high resistance to clinically relevant drugs which makes the antimicrobial therapy ineffective. We recently found that a pyridine compound is very active and we identified a mechanism of resistance, which relies on the extrusion of the new drug by RND-4 transporter. We characterized spontaneous resistant mutants in which RND-4 transcriptional regulator is impaired. Moreover, other resistant mutants were isolated and genome sequencing is in progress. As our results indicated that RND-4 made a significant contribution to the antibiotic resenocepacia, we are also performing heterologous expression trials of this transporter for future structural studies and drug design. RND (Resistance-Nodulation-Cell Division) efflux pumps are known to be among the mediators of multidrug resistance in Gam negative bacteria. Since the significance of the other 15 RND fflux systems present in B.cenocepacia (named RND-1 to -16) was only partially determined, another aim of our work is also to analyze mutants of B. cenocepacia strain J2315 inactivated in RND efflux systems, and assess their role in the efflux of toxic compounds. At the same time, different molecules both of natural origin and synthetic will be tested on B. cenocepacia J2315 in order to find new drugs and new targets to fight this pathogen.