The objective of this six-month Phase I SBIR proposal is to develop a new class of antibiotics based on inhibiting the bacterial DNA adenine methyltransferase. DNA methylation plays a critical role in the virulence of some bacteria, including E. coli and Salmonella typhimurium. Removing the enzyme by genetic means was shown to decrease virulence over 10,000 fold in animals. These results provide clear validation of this enzyme as a drug target. Humans lack this type of DNA methylation; thus, small molecules that inhibit the bacterial enzyme are likely to be selective. EpiGenX Pharmaceuticals now has an equipped lab that is engaged in discovering cancer therapeutics aimed at the mammalian DNA methyltransferase. A similar strategy is proposed here for E.coli DAM: high throughput fluorescence-based screens using purified E.coli DAM and two historical libraries. Using this strategy we have identified several potent inhibitors of the enzyme. We propose to use computational methods to facilitate our efforts to select the most potent compounds in the two historical libraries. Realization of the objective provides EpiGenX with a clear path for antibiotic optimization through more sophisticated focused combinatorial libraries, as well as animal studies to demonstrate in vivo efficacy.
Inhibitors of the bacterial DNA adenine methyltransferase, if shown to be potent antibiotics, hold grant promise in the fight against numerous infectious diseases. The commercialization of these drugs will require several years.
| Mashhoon, Neda; Pruss, Cynthia; Carroll, Michael et al. (2006) Selective inhibitors of bacterial DNA adenine methyltransferases. J Biomol Screen 11:497-510 |
| Mashhoon, Neda; Carroll, Michael; Pruss, Cynthia et al. (2004) Functional characterization of Escherichia coli DNA adenine methyltransferase, a novel target for antibiotics. J Biol Chem 279:52075-81 |
