Design, Synthesis, and Characterization of TNP-2198, a Dual-Targeted Rifamycin-Nitroimidazole Conjugate with Potent Activity against 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-targeted antibacterial agent for the treatment
of microaerophilic and anaerobic bacterial infections. TNP-2198 exhibits
greater activity than a 1:1 molar mixture of the parent drugs and
exhibits activity against strains resistant to both rifamycins and
nitroimidazoles. A crystal structure of TNP-2198 bound to a Mycobacterium tuberculosis RNA polymerase transcription
initiation complex reveals that the rifamycin portion of TNP-2198
binds to the rifamycin binding site on RNAP and the nitroimidazole
portion of TNP-2198 interacts directly with the DNA template-strand
in the RNAP active-center cleft, forming a hydrogen bond with a base
of the DNA template strand. TNP-2198 is currently in Phase 2 clinical
development for the treatment of Helicobacter pylori infection, Clostridioides difficile infection,
and bacterial vaginosis.