Abstract
With the spreading of antibiotic resistance, the translocation of antibiotics through bacterial envelopes is crucial for their antibacterial activity. In Gram-negative bacteria, the interplay between membrane permeability and drug efflux pumps must be investigated as a whole. Here, we quantified the intracellular accumulation of a series of fluoroquinolones in population and in individual cells of Escherichia coli according to the expression of the AcrB efflux transporter. Computational results supported the accumulation levels measured experimentally and highlighted how fluoroquinolones side chains interact with specific residues of the distal pocket of the AcrB tight monomer during recognition and binding steps.
Highlights
With the spreading of antibiotic resistance, the translocation of antibiotics through bacterial envelopes is crucial for their antibacterial activity
We previously showed that the molecular properties of three FQs dictate their capacity to accumulate in E. coli expressing or not the major multidrug efflux transporter AcrB, in complex with the adapter protein AcrA8,27
To determine how active efflux contributes to the antibacterial activity and intracellular accumulation of quinolone antibiotics, we selected nalidixic acid (NAL), flumequine (FLU), and 20 commercially available FQs
Summary
With the spreading of antibiotic resistance, the translocation of antibiotics through bacterial envelopes is crucial for their antibacterial activity. Numerous FQ derivatives have been synthesized by modifying the chemical structure of the 1,8 naphthyridine core in order to increase their antibacterial efficiency and improve their pharmacokinetics[16,17,18,19,20] These modifications have led to the synthesis of norfloxacin and ciprofloxacin, two antibiotics with increased activity against Gram-negative bacteria, which are still marketed[13]. Quinolone resistance is mostly due to mutational alteration of the drug targets that can be exacerbated concomitantly by a decreased outer-membrane permeability and an increased active efflux[8,12,16,21]. Our findings provide a robust correlation between internal drug concentration and efflux activity, which paves the way for the design of predictive FQ accumulation rules in Gram-negative bacteria
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