We have discovered a series of new mechanism antibiotics targeting Enterobacteriaceae, called DDS-04. Our DDS-04 series acts via LolCDE, a novel bacterial target. The LolCDE site of DDS-04 series activity is conserved in the majority of therapeutically important Enterobacteriaceae, resulting in targeted spectrum compounds. With its new mechanism of action, the DDS-04 series was rapidly bactericidal and highly potent across globally diverse Enterobacteriaceae strains in research studies,5 which included multi-drug resistant isolates. Importantly, the DDS-04 series also showed low propensity for resistance development and did not show cross-resistance with existing classes of antibiotics, suggesting that DDS-04 compounds have the potential to overcome known resistance mechanisms. This profile makes the DDS-04 series attractive for further development for the treatment of Enterobacteriaceae infections.
Our DDS-04 series compounds cured infection in a translationally-relevant animal model of urinary tract infection,5 one of the major sites for Enterobacteriaceae infection. Therapeutic concentrations of the DDS-04 compound were also observed in other major sites in the animal model where life-threatening Enterobacteriaceae infections occur, including the lungs and the bloodstream. Our initial pre-clinical candidate from the DDS-04 series is SMT-738.