Grant: Project Grant - PA: Antimicrobial Resistance (Bridge Grant)

Our interdisciplinary research team has developed and patented a new antibiotic class from a natural product, Tomatidine (TO). These novel molecules are potent broad-spectrum antibiotics. TM-184, our first lead candidate, demonstrated good activity against Gram-negative and Gram-positive bacteria. Moreover, efficacy in a mouse infection model was also demonstrated for TM-184 against E. coli. Although these results were very encouraging, compounds such as TM-184 present several medicinal chemistry challenges for pre-clinical development due to its cost and complexity. More recently, using computer-assisted drug design, we identified a novel class of small molecules with structural properties amenable to fast-track medicinal chemistry efforts. This series of molecules is much simpler, easier to synthesize, and less expensive. Inspired by the TM-184 series, we further improved its profile resulting in the identification of TM-397 which demonstrates good antibiotic properties for highly resistant bacteria strains. On the other hand, our preliminary studies demonstrated that this scaffold is amenable to potency, selectivity, and stability enhancements. Our research goal is to develop more selective, potent, and stable compounds that demonstrate effectiveness against difficult-to-treat and multiresistant bacteria not susceptible to existing resistance mechanisms for a clinical trials.