Antibiotic resistance is a growing health threat worldwide. Small-molecule screens that target specific complexes that are essential for bacterial metabolism will be useful in identifying new classes of microbial inhibitors. Bacterial RNase P represents an excellent target for developing novel anti-infectives: it is essential for viability of bacteria; it is well-characterized enzymatically and structurally; and it differs structurally and functionally from mammalian RNase P. Message Pharmaceuticals is dedicated to developing drugs that target RNA via post-transcriptional regulation. With its high-throughput capacity, Message has screened nearly 150,000 compounds for inhibitors of Neisseria gonorrhoeae RNase P. More than fifty compounds among six classes have exhibited dose-dependent inhibition of N. gonorrhoeae RNase P in vitro. Message proposes to develop these classes of leads further by: 1) determining their minimal inhibitory concentration endpoint against known bacterial isolates; 2) measuring the inhibition of RNase P enzymes from other evolutionarily diverse pathogenic bacteria; 3) comparing the inhibition to that of human RNase P; 4) assessing cytotoxicity in mammalian cells in culture. In addition to identifying novel anti-infectives, the results will advance our understanding of the function of an evolutionarily ancient RNA enzyme, and, more importantly, reveal new classes of small molecules that interact with structured RNAs.
With the worldwide emergence and expansion of antibiotic resistance in both the nosocomial and community settings, new classes of antibiotics are needed to combat the resistance. The results from this grant will contribute to the development of novel classes of antibiotics for a variety of resistant bacterial infections.
