Re-sensitization of Multidrug-Resistant and Colistin-Resistant Gram-Negative Bacteria to Colistin by Povarov/Doebner-Derived Compounds.

Colistin, typically viewed as the antibiotic of last resort to treat infections caused by multidrug-resistant (MDR) Gram-negative bacteria, had fallen out of favor due to toxicity issues. The recent increase in clinical usage of colistin has resulted in colistin-resistant isolates becoming more common. To counter this threat, we have investigated previously reported compounds, and , and developed 13 compounds with more desirable drug-like properties for colistin sensitization against 16 colistin-resistant bacterial strains, three of which harbor the plasmid-borne mobile colistin resistance (). Lead compound , which has a lower LogD (2.46) compared to (>5.58), reduces the minimum inhibitory concentration (MIC) of colistin against strain TRPA161 to 0.03 μg/mL from 1024 μg/mL (34,000-fold reduction). Checkerboard assays revealed that and analogues are also synergistic with colistin against colistin-resistant strains of , , and . Preliminary mechanism of action studies indicate that exerts its action differently depending on the bacterial species. Time-kill studies suggested that in combination with 0.5 μg/mL colistin was bactericidal to extended-spectrum beta-lactamase (ESBL)-producing , as well as to harboring , while against TRPA161, the combination was bacteriostatic. Mechanistically, increased membrane permeability in harboring a plasmid containing the gene but did not increase radical oxygen species (ROS), while a combination of 15 μM and 0.5 μg/mL colistin significantly increased ROS in TRPA161. was not toxic to mammalian red blood cells (up to 226 μM).