Novel DNA Polymerase Inhibitors as Gram-Positive Antibacterial Agents

The alarming increase in incidence of infections caused by drug-resistant bacteria has created an urgent need for new antibacterial agents. We have discovered and optimized a novel class of antibiotics targeting PolC, the replicative DNA polymerase in Gram-positive bacteria. These agents exhibit broad spectrum activity against Gram-positive bacteria, including clinically important pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), Streptococcus pyogenes (Group A strep), vancomycin-resistant enterococcus (VRE) and Clostridium difficile. In addition, compounds of this class are currently being evaluated for antibacterial activity in Gram-positive biothreat pathogens such as Bacillus anthracis. <P>These agents demonstrate bactericidal activity, oral bioavailability, in vivo efficacy, a low propensity for toxicity and a low rate of spontaneous resistance. The mechanism of action has been unambiguously defined: the compounds inhibit an essential and novel molecular target involved in bacterial DNA synthesis and consequently circumvent existing mechanisms of antibiotic resistance. Although mechanistically similar to previously described PolC inhibitors of the anilino uracil class (Daly et al., 2000, Antimicrob. Agents Chemother. 44:2217), this compound series is chemically distinct, and displays more favorable microbiological potency and more desirable physical properties for drug development.<P> We seek funding to advance this program from its current preclinical stage of lead optimization to the point of selecting a candidate compound for clinical development. The research plan leading to Investigational New Drug (IND) candidate selection comprises three stages. <P>First, we will leverage information from our current structure- activity relationship (SAR) data coupled with a collection of 15 target-inhibitor co-crystals to perform structure- based lead optimization. Resulting compounds will be synthesized and will undergo extensive microbiological profiling. Compounds meeting the desired thresholds for potency and selectivity will progress to the second step, consisting of in vitro screens for metabolic stability and toxicity. This includes measuring degradation rates in human liver microsomes in order to estimate oral bioavailability and overall plasma exposure levels.<P> Receptor binding assays that are predictive of known toxicity pathways have proven utility and help to ensure that the promising safety profile of these compounds is maintained throughout the lead optimization process. Compounds that pass the in vitro screens will progress to the final stage, consisting of in vivo testing of pharmacokinetics, efficacy and preliminary multi-dose toxicity. Collectively, these data should provide a detailed characterization of several lead compounds, supporting selection of the final IND candidate.<P> A successful outcome would provide a long-term public health benefit in combating the rising tide of antibiotic- resistant infections that pose an acute threat to the general population, even those without predisposing risk factors.