INHIBITION OF SIGNAL PEPTIDASE DEPENDENT SECRETED PROTEINS BY ARYLOMYCIN

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. During the previous award period, we identified bacterial proteins whose inhibition would prevent the evolution of antibiotic resistance-conferring mutations, and also used high-throughput screens to identify lead compounds that inhibit the identified protein targets. We refer to the compounds as ?antibiotics? (because they should kill bacteria in the context of an infection) but also as ?achaogens? (because they should inhibit the evolution of resistance). Such compounds might have important uses as a co-therapy with traditional antibiotics or on their own. In this Renewal Application, we seek funds to further evaluate these lead compounds biochemically and begin to define therapeutic applications where they may be useful. Specifically we will focus on defining the ability of our lead compounds to inhibit mutation and also to kill bacteria in the context of several important infections. We also propose the extension of the achaogen concept to include inhibitors of lateral transfer, another major route by which bacteria evolve resistance to antibiotics. Our preliminary results include the synthesis and identification of several small molecules that inhibit lateral transfer via the inhibition of type I signal peptidase (SPase), which is required for the assembly of the type IV secretion systems that mediate lateral transfer. We have shown that a class of penems inhibit SPase and lateral transfer in vivo, as does a class of natural products known as the arylomycins. Because SPase is also required for the export of most surface displayed or secreted proteins, its inhibition, like that of RecA, should dramatically reduce bacterial virulence. We thus also seek funds to optimize the penem and arylomycin compounds as antibiotic/achaogens. The major deliverables of the proposed research are thus at least one class of antibiotic/achaogen that acts via the inhibition of RecA, and one that acts via the inhibition of SPase.