Preclinical Development of Pentamidine Analogs Identifies a Potent and Nontoxic Antibiotic Adjuvant br

The difficulty in treating Gram-negative bacteria can largely be attributed to their highly impermeable outer membrane(OM), which serves as a barrier to many otherwise active antibiotics. This can be overcome with the use of perturbantmolecules, which disrupt OM integrity and sensitize Gram-negativebacteria to many clinically available Gram-positive-active anti-biotics. Although many new perturbants have been identified inrecent years, most of these molecules are impeded by toxicity dueto the similarities between pathogen and host cell membranes. Forexample, our group recently reported the cryptic OM-perturbing activity of the antiprotozoal drug pentamidine. Its development asan antibiotic adjuvant is limited, however, by toxicity concerns. Herein, we took a medicinal chemistry approach to develop novelanalogs of pentamidine, aiming to improve its OM activity while reducing its off-target toxicity. We identified the compound P35,which induces OM disruption and potentiates Gram-positive-active antibiotics inAcinetobacter baumanniiandKlebsiella pneumoniae.Relative to pentamidine, P35 has reduced mammalian cell cytotoxicity and hERG trafficking inhibition. Additionally, P35outperforms pentamidine in a murine model ofA. baumanniibacteremia. Together, this preclinical analysis supports P35 as a promising lead for further development as an OM perturbant.