The challenge of intracellular antibiotic accumulation, a function of fluoroquinolone influx versus bacterial efflux

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.

Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria

“…Although none of the compounds significantly reduced MIC values of antibiotics in K. aerogenes strains, several of them exerted a potent 1,2’-dNA efflux inhibition (up to 90 % for compound 19 ) in the RTE assay. A recent study has analyzed the molecular and kinetic, e.g., accumulation and efflux, parameters of various fluoroquinolone efflux in E. coli expressing different levels of AcrAB [ 52 ]. The efflux index (SICAR: Structure Intracellular Concentration Activity Relationship) determined for each fluoroquinolone clearly demonstrates the key role of antibiotic side chains and internal residues of AcrB in the transporter affinity and in the efficiency of drug translocation across the expel channel [ 52 ].…”

“…A recent study has analyzed the molecular and kinetic, e.g., accumulation and efflux, parameters of various fluoroquinolone efflux in E. coli expressing different levels of AcrAB [ 52 ]. The efflux index (SICAR: Structure Intracellular Concentration Activity Relationship) determined for each fluoroquinolone clearly demonstrates the key role of antibiotic side chains and internal residues of AcrB in the transporter affinity and in the efficiency of drug translocation across the expel channel [ 52 ]. Consistently, the adjuvant potential reflects the strength of the affinity AcrB-substrate and depends on the molecular interaction between the partners, e.g., AcrB-antibiotic and AcrB-adjuvant.…”

Targeting Salmonella Typhimurium Invasion and Intracellular Survival Using Pyrogallol

“…The accumulation of fluoroquinolone in intact bacteria was determined as previously described ( Vergalli et al, 2020 ) using ciprofloxacin due to its increased yield of fluorescent signal intensity. Salmonella Typhimurium was grown at 37°C in LB to mid-exponential phase.…”

A multivariate comparative clinical pharmacotherapeutic efficacy and chronopharmacovigilance assessment study of ofloxacin, one of the commonplace, TGFβ1 inducing and telomerase impairing fluoroquinolones, in treating acute gastroenteritis, chronic obstructive pulmonary disease, new drug-sensitive tuberculosis, recurrent mixed cutaneous infections, and post-surgical refractory wound infections, among the global patients, with heterogenous pharmacogeographic and pharmacogenomic constitution

“…This study re-emphasised, with all its investigative aspects, that ofloxacin was, is, and would always remain an extremely necessary 'essential drug', as it has numerous therapeutic uses, high efficacy, confirmed safety, easy availability and accessibility, and suitability in both acute and chronic complicated disease conditions; shown also in several studies, performed throughout the world. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] The initial quinolone compounds had a limited spectrum of activity against gram negative organisms thus, restricting their clinical use. To the core quinolone ring structure, addition of moieties like fluorine at C6 and piperazinyl at C7, increased the gram-negative coverage and improved the systemic retention of the drugs.…”

“…The findings provide a robust correlation between internal drug concentration and efflux activity, which paves the way for the design of predictive fluoroquinolone accumulation rules in gram-negative bacteria. 14 In another study, the aim of the research was to synthesize novel fluoroquinolones and evaluate their in vitro antilipolytic and antiproliferative properties. Characterization of the synthesized fluoroquinolones was carried out with NMR, MS, IR, and EA.…”