Chandler Pilot Project Summary

The bacterium Burkholderia pseudomallei is the causative agent of melioidosis, a human disease that is quite difficult to treat and contributes to about 90,000 deaths worldwide per year. Despite the increasing incidence of melioidosis, this pathogen is poorly understood in terms of its basic biology and this deficit remains a barrier to developing new therapies to treat melioidosis. Our long-term goal is to define the underlying mechanisms of B. pseudomallei virulence, and use this information to identify novel therapeutic interventions to treat this challenging human disease. This proposal is focused on a B. pseudomallei small-molecule toxin, malleilactone, which plays an important role in B. pseudomallei pathogenesis. The particular function of malleilactone has remained elusive, in part because it has been difficult to produce in standard laboratory conditions and also because its purification has remained problematic. However, recent approaches involving genetic and chemical means to elicit production of malleilactone, and production of highly pure malleilactone through the KU COBRE SCB Core, facilitated a new line of experimentation to understand exactly how malleilactone functions in the cell. Preliminary studies indicate malleilactone coordinates with iron, and promotes growth in iron-depleted conditions such as that encountered during host infections. The mechanism appears to be unique from that of other known siderophores that scavenge iron. Our studies also show malleilactone can be self-toxic under certain conditions, and that this toxicity is abrogated by an antibiotic efflux pump that contributes to the export of malleilactone. The central hypothesis of this proposal is that malleilactone benefits the cell under conditions where iron is limited and causes self-toxicity in conditions where resistance is impaired. The pilot experiments proposed here aim to 1) elucidate the role of malleilactone in scavenging iron and 2) establish the role of efflux pumps in preventing self-toxicity. These results are essential to gain a mechanistic understanding of how malleilactone contributes to B. pseudomallei infections in the host, and might ultimately lead to development of new therapeutics to treat melioidosis.