Quinolones: Mechanism, Lethality and Their Contributions to Antibiotic Resistance

Abstract

Fluoroquinolones (FQs) are arguably among the most successful antibiotics of recent times. They have enjoyed over 30 years of clinical usage and become essential tools in the armoury of clinical treatments. FQs target the bacterial enzymes DNA gyrase and DNA topoisomerase IV, where they stabilise a covalent enzyme-DNA complex in which the DNA is cleaved in both strands. This leads to cell death and turns out to be a very effective way of killing bacteria. However, resistance to FQs is increasingly problematic, and alternative compounds are urgently needed. Here, we review the mechanisms of action of FQs and discuss the potential pathways leading to cell death. We also discuss quinolone resistance and how quinolone treatment can lead to resistance to non-quinolone antibiotics.

Presence of Chromosomal crpP-like Genes Is Not Always Associated with Ciprofloxacin Resistance in Pseudomonas aeruginosa Clinical Isolates Recovered in ICU Patients from Portugal and Spain

“…In consistence with previous studies, the most frequent resistance mechanism to quinolones in our MDR/XDR P. aeruginosa sequenced isolates was the presence of mutations in the gyrA and parC genes, encoding gyrase and topoisomerase IV subunits [ 4 ]. Additionally, the horizontally transferred genes qnrS2 and aac ( 6′)-Ib-cr were eventually detected in relation to certain clones.…”

“…Resistance to quinolones usually results from mutational alterations in drug target affinity, efflux pumps and/or porin channels overexpression, and acquisition of resistance-conferring genes [ 3 ]. Chromosomal mutational resistance affecting fluroquinolones mainly occurs in the so-called quinolone resistance determining region (QRDR) of topoisomerases [ 4 ]. Moreover, plasmid-mediated quinolone resistance (PMQR) has been also described and is generally due to Qnr-type proteins, the aminoglycoside-modifying enzyme AAC(6′)-Ib-cr acetyltransferase and mobile efflux systems such as QepA or OqxAB [ 5 ].…”

Mixed Pluronic—Cremophor Polymeric Micelles as Nanocarriers for Poorly Soluble Antibiotics—The Influence on the Antibacterial Activity

“…The advantages of these nanoparticulate carriers in antimicrobial formulations include targeted delivery to the infection site, improved cellular internalization and drug stability, higher solubility, and sustained drug release [1]. The quinolone and their derivatives fluoroquinolone antibiotics are the most efficient class of topoisomerase inhibitors, used to treat bacterial infections caused by both Gram-positive and Gram-negative bacteria [2]. Their mechanism of action consists in the inhibition of topoisomerase enzymes (DNA gyrase implicated in genome replication and transcription), which inhibits the relaxation of supercoiled DNA and promotes the breakage of double stranded DNA [3].…”

Topoisomerase VI is a chirally-selective, preferential DNA decatenase

“…These enzymes are vital during DNA metabolism, particularly in the relief of torsional stress built up ahead of and behind the transcription complexes and replication forks, as well as the removal of catenanes and knots (3)(4)(5). For this reason, targeting the topos as a means to treat bacterial infections and cancer has had significant and ongoing clinical success (6)(7)(8)(9).…”