Due to the widespread emergence of drug-resistance, diseases caused by bacterial pathogens have become a major public health concern in recent years. There is an urgent need for the development of new antimicrobials, especially those that have a new target and/or can overcome drug resistance. The long-term goal of this project is the development of novel antimicrobial agents that inhibit SecA, an indispensable ATPase of the protein translocation machinery present in all bacteria. SecA is responsible for the secretion of many vital proteins, important toxins and other virulence factors, and is essential for bacterial survival. SecA has no counterpart in mammalian cells, thus providing an ideal target for developing antimicrobial agents. We hypothesize that inhibition of this essential protein would lead to hindered bacterial growth and/or viability. Moreover, SecA functions as a membrane protein, forming a transmembrane channel, and thus provides the possibility for antimicrobial agents to reach this target without entering into the cells. Therefore, these inhibitors may have the intrinsic ability to overcome the effect of efflux pumps and thus multi-drug resistance (MDR). In addition, because SecA is present in all bacteria, this is a target for the development of broad-spectrum antimicrobials. Indeed, our preliminary results support all these hypotheses. In this project, we plan to examine the mechanistic issues aimed at examining the feasibility of targeting SecA for the development of potential antimicrobial agents. The project is based on strong preliminary results including our finding of very promising antimicrobial agents that inhibit SecA and show more potent activities than known drugs such as vancomycin on drug resistant strains of bacteria, and a strong team of investigators that have had a long collaboration history. Successful completion of the proposed research will lay a strong foundation for future development of novel antimicrobials that have a new mechanism of action and have the potential to overcome efflux-mediated drug resistance.
