METAL TRANSPORTERS · Mechanistic and Pharmacological studies of transition-metal ABC transporters that are essential to bacterial virulence

In the past 20 years, we have witnessed a constant rise in bacterial resistance to antibiotics. Paradoxically, this has been accompanied by an almost complete exodus of pharmaceutical companies from the antibiotics market. As a result we are facing a situation where our antibacterial toolkit is much depleted and outdated. The goal of the proposed research is to address this deficiency by studying a group of potentially promising novel antibiotic targets: ATP Binding Cassette (ABC) transporters of transition metals.In many clinically important bacterial pathogens (e.g. Streptococcus pneumonia, Mycobacterium tuberculosis, Salmonella typhi) ABC transporters of transition metals have been shown to be essential for virulence/pathogenesis. Remarkably, beyond these observations, little else is known of these systems. We propose to study, and develop inhibitors towards 3 uncharacterized transition metal ABC transport systems that are essential to pathogenesis: ZnuABC of Salmonella typhi, sloABC of Streptococcus pneumonia, and the newly identified Bacillus anthracis (Anthrax) virulence determinant MntABC.Our proposal is comprised of two parts: the first is an in-depth functional analysis of these transporters, aimed at understanding their molecular mechanism. Our second goal, which is inseparable from the first, is to develop inhibitors for these transport systems, laying the foundations for future antibiotic development.