In vitro and in vivo studies of novel antimicrobials targeting bacterial cytoskeleton and cell surface virulence markers in the treatment of Burkholderia cepacia complex infection

The Burkholderia cepacia complex (Bcc) comprises opportunistic pathogens in CF patients whose unifying theme is the high level of antibiotic resistance. Lung transplantation is the only treatment that improves both the quantity and quality of life of CF patients with advanced lung disease. It has been shown that Bcc infections are the second most common infection in CF prior to transplantation. A dramatic drawback of Bcc infections is that they limit the selection of CF patients for lung transplantation because of the high risk of post-operative death; poor outcomes are common in those patients with pre-operative B. cenocepacia infection. New antimicrobial compounds with activity against the Bcc are needed. The bacterial cytoskeleton has emerged as a new target for antimicrobials. We hypothesize the bacterial cytoskeleton plays a central role in the assembly and organization of macromolecular protein complexes including those important in pathogenicity. The cytoskeleton inhibitors alter the bacterial membrane, comprising virulence factors involved in pathways controlling inflammation and host defences as lipopolysaccharides. The comprehension of such induced modifications can contribute to understand how bacteria adapt and respond to antimicrobial compounds, which are the secondary alterations induced by cytoskeleton inhibitors and their effect on bacterial viability and virulence. In this frame, to set up new antibacterial therapies, this project is aimed to: the elucidation of the in vitro and in vivo antimicrobial activity of such bacterial cytoskeleton inhibitors on clinically derived Bcc strains from patients undergoing lung transplantation with Bcc infections; analysis of secondary effects of these cytoskeleton inhibitors on bacterial membrane including changes in Lipopolysaccharide composition, structure and biological activity; assessment of the in vivo antimicrobial activity and host toxicity of novel cytoskeleton inhibitors in the murine model of acute and chronic infection.