Abstract
Fluoroquinolones (FQs) are broad-spectrum antibiotics largely used in the clinical practice against Gram-negative and some Gram-positive bacteria. Nevertheless, bacteria have developed several antimicrobial resistance mechanisms against such class of antibiotics. Ternary complexes of FQs, copper(II) and phenanthroline, known as metalloantibiotics, arise in an attempt to counteract an antibiotic resistance mechanism related to low membrane permeability. These metalloantibiotics seem to use an alternative influx route, independent of porins. The translocation pathways of five FQs and its metalloantibiotics were studied through biophysical experiments, allowing us to infer about the role of OmpF porin in the influx. The FQ-OmpF interaction was assessed in mimetic membrane systems differing on the lipidic composition, disclosing no interference of the lipidic composition. The drug-porin interaction revealed similar values for the association constants of FQs and metalloantibiotics with native OmpF. Therefore, OmpF mutants and specific quenchers were used to study the location-association relationship, comparing a free FQ and its metalloantibiotic. The free FQ revealed a specific association, with preference for residues on the centre of OmpF, while the metalloantibiotic showed a random interaction. Thereby, metalloantibiotics may be an alternative to pure FQs, being able to overcome some antimicrobial resistance mechanism of Gram-negative bacteria related to decreased membrane permeability.
Highlights
IntroductionOutbreaks of infectious diseases and environmental hazards antimicrobial resistance (AMR) is one of the major public health threats of the 21st century, [1,2]
Received: 26 November 2020 Accepted: December 2020 Published: December 2020Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.Together with epidemics, outbreaks of infectious diseases and environmental hazards antimicrobial resistance (AMR) is one of the major public health threats of the 21st century, [1,2]
The reduction of the intracellular concentration of drugs is one of the main bacterial resistance mechanisms developed against antibiotics
Summary
Outbreaks of infectious diseases and environmental hazards antimicrobial resistance (AMR) is one of the major public health threats of the 21st century, [1,2]. The inner leaflet is mostly composed by phospholipids, being extremely similar to the cytoplasmic membrane [10]. This leaflet harbours lipoproteins (attached to lipids) and integral membrane proteins, known as outer membrane proteins (Omps) or porins [9,12]. These channels are responsible for the transport of nutrients and some antibiotics as FQs or β-lactams [11,13,14]
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