Multivalent Display of Lipophilic DNA Binders for Dual-Selective Anti-Mycobacterium Peptidomimetics with Binary Mechanism of Action

We made oligoamidine-based peptidomimetics highly specific for mycobacteria eradication by introducing and arraying lipophilic DNA binding motifs on macromolecular backbones. The short poly(amidino-phenylindole) (PAPI) structures feature an alternating amphiphilic structure with cationic, lipophilic DNA-binding moieties, enabling fast and selective eradication of mycobacteria through binary, membrane- and DNA-selective mechanisms of action. More importantly, PAPIs address the primary treatment challenge by combating mycobacteria in eukaryotic cells and working as a sensitizer for conventional antibiotics, in bothways promoting more thorough removal of pathogens and reducing the mycobacteria's resistance generation rate during treatment. Structural optimizationwas achieved to counter specific pathogens, including Mycobacterium tuberculosis, in the Mycobacterium genus. One of the hit peptidomimetics was evaluated in a zebrafish-based aquatic infection model using Mycobacterium fortuitum and a mice tail infection model using Mycobacterium marinum, both revealing excellent in vivo performance.