Designing Antibiotics with Inherent Resistance to Efflux as a Strategy to Revive Discovery against...

We report a novel Efflux Resistance Breaker (ERB) strategy for designing antibiotics intrinsically resistant to efflux, using fluoroquinolones as a model class. ERB-modified fluoroquinolones showed enhanced intracellular accumulation and markedly improved antibacterial activity, with up to 512-fold reduction in MIC (MIC₉₀ 0.03-2 μg/mL) across multidrug-resistant bacteria. Lead compounds KSN-L22 (46) and BL-7 (50) demonstrated potent activity against MRSA, Streptococcus pneumoniae (including MDR and PRSP), Enterococcus faecalis and E. faecium (VanA, VanB and VanD), as well as Acinetobacter baumannii and Escherichia coli. The compounds inhibited both wild-type and S84L mutant DNA gyrase (IC₅₀ ∼ 3.8 μg/mL) and achieved a > 4-log bacterial load reduction in a murine thigh infection model at oral doses of 50 mg/kg. Favorable oral and intravenous PK/PD profiles, absence of toxicity at 1200 mg/kg/day, and no hERG, CYP450, or off-target liabilities were observed. ERB technology provides a promising strategy for designing antibiotics that are intrinsically less susceptible to efflux.