ZTW-41, a Potent Indolizinoquinoline-5,12-Dione Derivative Against Drug-Resistant and Bacteria.

ZTW-41, an indolizinoquinoline-5,12-dione derivative, was investigated for antibacterial activity against Gram-positive bacteria, especially methicillin-resistant (MRSA). In our study, the MICs (minimum inhibitory concentrations) of ZTW-41 against MRSA (MRSA,  = 200), methicillin-sensitive (MSSA,  = 100), (,  = 32), and ( = 32) were 0.25, 0.25, 0.125, and 8 μg/mL, respectively, whereas the MBCs (minimum bactericidal concentrations) were 2, 1, 1, and >32 μg/mL, respectively. ZTW-41 maintained its potency at different pH levels (range 5-9) and in starting inoculum size up to 10 CFU/mL. The presence of human serum (25-75%) increased ZTW-41 MICs by two- to eightfold. Time-kill curves showed that ZTW-41 had bactericidal activity against MRSA, MSSA, and strains within 8 hours, and rebound growth occurred after 8 hours except at higher multiples of the MIC (4 × and 8 × ). In the acute toxicity study, no mortality or signs of toxicity was noted in mice after 14 days of observation at doses <50 mg/kg. ZTW-41 exhibited good selectivity indices (SIs) (SI = IC/MIC) ranging from 1.12 to 71.76 against clinical isolates, demonstrating excellent therapeutic selectivity in MRSA, MSSA, and strains. Moreover, the efficacy (effective dose [ED] = 6.59 mg/kg) of ZTW-41 was found comparable with vancomycin. Collectively, our favorable results supported ZTW-41 as a promising investigational candidate for treating drug-resistant bacteria infection.