Efflux resistance breakers: a new technology to overcome efflux-mediated resistance in multidrug resistant bacteria

We have developed a novel approach to reduce efflux liability in different antibiotic classes, based on advanced structural modelling, identification of “efflux-resistance breaker” (ERB) pharmacophores, and detailed understanding of efflux liability in multidrug resistant (MDR) pathogens. This technology allows development of antimicrobials that are less susceptible to efflux and do not require the use of additional efflux pump inhibitors. These ERB-modified antibiotics maintain high intracellular concentrations resulting in bacterial death, even in the presence of multiple target mutations associated with resistance. The ERB-fluoroquinolones show notably better activity compared to parent fluoroquinolones in a variety of MDR bacteria with up to a 512-fold reduction in MIC (MIC90 0.03 to 2 µg/mL). The lead compounds, KSN-L22 and BL-7 showed MICs of 0.03 to 0.5 µg/mL against MRSA, 0.03 to 2 µg/mL against Acinetobacter baumannii, 0.03 to 2 µg/mL against Escherichia coli and 0.25 to 4 µg/mL against Klebsiella pneumoniae strains. The ERB-fluoroquinolones work by inhibiting both wild type and mutant (GyrA S84L) DNA gyrases (IC50 ~3.8 µg/mL). Both BL-7 and KSN-L22 showed in vivo efficacy in a thigh infection model with 5-log reduction of bacterial load at both 20 and 50 mg/kg oral dose levels and excellent oral and IV PK/PD profiles. The compounds did not show any toxicity at 1200 mg/kg/day in mice. The off-target toxicity screen did not reveal any issues, including the hERG channel, and the compounds do not induce or inhibit cytochrome p450 enzymes. Use of efflux resistance breaker technology to make the compounds less susceptible to efflux has the potential to revive the use of several classes of current antibiotics. 

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