Designing Antibiotics with Inherent Resistance to Efflux as a Strategy to Revive Discovery against
Mark Laws1, Charlotte K Hind2, Kazi Sharmin Nahar1,3
1School of Cancer and Pharmaceutical Sciences, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, U.K.
Journal of Medicinal Chemistry
|May 29, 2026
Summary
A new Efflux Resistance Breaker (ERB) strategy creates antibiotics resistant to efflux pumps. This approach enhances fluoroquinolone accumulation and activity against multidrug-resistant bacteria, offering a promising solution for antibiotic development.
Area of Science:
- Antimicrobial resistance
- Medicinal chemistry
- Drug discovery
Background:
- Bacterial efflux pumps are a major mechanism of multidrug resistance (MDR).
- Fluoroquinolones are a critical class of antibiotics often rendered ineffective by efflux pumps.
- Novel strategies are needed to overcome efflux-mediated resistance in bacteria.
Purpose of the Study:
- To develop a novel Efflux Resistance Breaker (ERB) strategy for designing intrinsically efflux-resistant antibiotics.
- To utilize fluoroquinolones as a model class to demonstrate the ERB strategy's efficacy.
- To evaluate the antibacterial activity and safety profiles of ERB-modified fluoroquinolones.
Main Methods:
- Design and synthesis of novel fluoroquinolone derivatives incorporating the ERB strategy.
- In vitro evaluation of antibacterial activity against a panel of multidrug-resistant bacteria, including determination of Minimum Inhibitory Concentrations (MICs).
- In vivo assessment of efficacy in a murine thigh infection model and evaluation of pharmacokinetic/pharmacodynamic (PK/PD) profiles and toxicity.
Main Results:
- ERB-modified fluoroquinolones exhibited enhanced intracellular accumulation and significantly reduced MICs (up to 512-fold reduction) against MDR bacteria.
- Lead compounds KSN-L22 and BL-7 showed potent activity against Gram-positive and Gram-negative pathogens, including MRSA, MDR Streptococcus pneumoniae, and resistant Enterococcus and Escherichia coli strains.
- Compounds demonstrated efficacy in a murine thigh infection model, favorable PK/PD profiles, and no observed toxicity or off-target liabilities.
Conclusions:
- The Efflux Resistance Breaker (ERB) strategy is a viable approach for developing antibiotics with intrinsic resistance to efflux pumps.
- ERB-modified fluoroquinolones represent a promising new class of antibiotics effective against challenging multidrug-resistant bacterial infections.
- This technology has broad applicability for overcoming efflux-mediated resistance in antibiotic design.
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