Background Burkholderia cepacia complex (BCC) bacteria are opportunistic pathogens which cause severe lung infections in cystic fibrosis (CF) patients. Treatment of BCC infections is difficult due to the inherent multidrug resistance of BCC. There is a pressing need to find new bacterial targets for antimicrobials that provide functions essential for cell growth & replication. A major component of the bacterial cytoskeleton is the actin homologue MreB. MreB maintains bacterial cell shape by forming filaments under the bacterial inner membrane. A22 is a cell permeable compound that disrupts MreB, destabilising the bacterial cytoskeleton and altering the bacterial shape.
Aims To investigate the MreB bacterial cytoskeleton as a novel target for antimicrobials.
Methods We have tested a synthetic library of A22-related compounds and identified compound Q22 as a potential antimicrobial of interest against BCC and Pseudomonas aeruginosa strains. BCC bacteria have been grown in the presence of Q22 and a number of phenotypic changes observed.
Results Q22 inhibited growth of all 9 BCC species tested, including B. cenocepacia. A reduction in growth rate and cell morphology changes were also observed (Abstract S20 Figure 1). Higher concentrations of Q22 were required to exert B. cenocepacia growth effects (30 μg/ml Q22) when compared to P. aeruginosa (3 μg/ml Q22), probably due to the presence of two mreB genes in the B. cenocepacia genome. BCC bacteria lipopolysaccharide (LPS) is known to play an important role during infection. We analysed the LPS profile of BCC bacteria grown in the presence of Q22 and selected strains show profile differences when compared to untreated bacteria. The influence of Q22 treatment on bacterial motility and Type 3 secretion, a virulence associated secretion system, was assessed. However, growth inhibition masked motility analysis and differences observed in secreted protein profiles could not be attributed to Type 3 secretion. The growth conditions required for induction of Type 3 secretion in vitro remain undefined.
Conclusion In vitro MreB is an attractive new target for novel antimicrobials. Further analysis of current observations and additional phenotypic analysis will be required to dissect the nature of Q22-induced changes. Work supported by Newcastle-Upon-Tyne Hospitals Special Trustees and Italian CF Research Foundation (FFC).
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