Design, Synthesis, and Characterization of TNP-2198, a Dual-Targeted Rifamycin-Nitroimidazole Conjugate with Potent Activityagainst Microaerophilic and Anaerobic Bacterial Pathogens

TNP-2198, a stable conjugate of a rifamycin pharmacophore and a nitroimidazole pharmacophore, has been designed, synthesized, and evaluated as a novel dual-targetedantibacterial agent for the treatment of microaerophilic andanaerobic bacterial infections. TNP-2198 exhibits greater activitythan a 1:1 molar mixture of the parent drugs and exhibits activityagainst strains resistant to both rifamycins and nitroimidazoles. Acrystal structure of TNP-2198 bound to aMycobacteriumtuberculosisRNA polymerase transcription initiation complexreveals that the rifamycin portion of TNP-2198 binds to therifamycin binding site on RNAP and the nitroimidazole portion ofTNP-2198 interacts directly with the DNA template-strand in the RNAP active-center cleft, forming a hydrogen bond with a base ofthe DNA template strand. TNP-2198 is currently in Phase 2 clinical development for the treatment of Helicobacter pyloriinfection, Clostridioides difficile infection, and bacterial vaginosis