Mechanisms of quinolone action and resistance: where do we stand?

Abstract

Quinolone antibiotics represent one of the most important classes of anti-infective agents and, although still clinically valuable, their use has been compromised by the increasing emergence of resistant strains, which has become a prevalent clinical problem. Quinolones act by inhibiting the activity of DNA gyrase and topoisomerase IV - two essential bacterial enzymes that modulate the chromosomal supercoiling required for critical nucleic acid processes. The acquisition of quinolone resistance is recognized to be multifactorial and complex. The main resistance mechanism consists of one or a combination of target-site gene mutations that alter the drug-binding affinity of target enzymes. However, other mechanisms such as mutations that lead to reduced intracellular drug concentrations, by either decreased uptake or increased efflux, and plasmid-encoded resistance genes producing either target protection proteins, drug-modifying enzymes or multidrug efflux pumps are known to contribute additively to quinolone resistance. The understanding of these different resistance mechanisms has improved significantly in recent years; however, many details remain to be clarified and the contribution of less-studied mechanisms still needs to be better elucidated in order to fully understand this phenotype.

Asiatic Acid (AA) Sensitizes Multidrug-Resistant Human Lung Adenocarcinoma A549/DDP Cells to Cisplatin (DDP) via Downregulation of P-Glycoprotein (MDR1) and Its Targets

“…Many studies have addressed drug resistance mechanisms, which can be classified into two classes [33]: one is the genetic and epigenetic alternations of tumor cells that affect drug sensitivity; the other is impairment of the drug delivery system of tumor cells. In this study, we found that downregulation of P-gp by AA effectively increased the drug sensitivity of A549/DDP cells.…”

Resistome, Mobilome and Virulome Analysis of Shewanella algae and Vibrio spp. Strains Isolated in Italian Aquaculture Centers

“…Then, their association to plasmids has allowed their spread in other bacterial species. It is noted that PMQR determinants generally confer only low-level quinolone resistance that alone does not exceed the clinical breakpoint but they can favor the selection of additional resistance mechanisms [70].…”

BceAB-Type Antibiotic Resistance Transporters Appear To Act by Target Protection of Cell Wall Synthesis

“…This mode of resistance has been collectively termed "target protection" and generally involves the direct release of a cellular target from the inhibitory action of the antibiotic (41,42). Target protection has been reported for the ribosome and DNA replication (43)(44)(45), but to our knowledge, no example has been described to date for the protection of cell wall synthesis. We now propose that BceAB-type transporters act by target protection of the lipid II cycle.…”