Quinolone antibiotics

Abstract

The quinolone antibiotics arose in the early 1960s, with the first examples possessing a narrow-spectrum of activity with unfavorable pharmacokinetic properties. Over time, the development of new quinolone antibiotics has led to improved analogues with an expanded spectrum and high efficacy. Nowadays, quinolones are widely used for treating a variety of infections. Quinolones are broad-spectrum antibiotics that are active against both Gram-positive and Gram-negative bacteria, including mycobacteria, and anaerobes. They exert their actions by inhibiting bacterial nucleic acid synthesis through disrupting the enzymes topoisomerase IV and DNA gyrase, and by causing breakage of bacterial chromosomes. However, bacteria have acquired resistance to quinolones, similar to other antibacterial agents, due to the overuse of these drugs. Mechanisms contributing to quinolone resistance are mediated by chromosomal mutations and/or plasmid gene uptake that alter the topoisomerase targets, modify the quinolone, and/or reduce drug accumulation by either decreased uptake or increased efflux. This review discusses the development of this class of antibiotics in terms of potency, pharmacokinetics and toxicity, along with the resistance mechanisms which reduce the quinolones' activity against pathogens. Potential strategies for future generations of quinolone antibiotics with enhanced activity against resistant strains are suggested.

This journal is © The Royal Society of Chemistry 2019.

Figures

Fig. 1. Core structure of quinolone antibiotics. There are 6 important positions for modifications to improve the activity of the drug: R1, R5, R6, R7, R8, and X. X = C defines quinolones, X = N defines naphthyridones.

Fig. 2. The structure–activity relationships (SAR) of quinolones. The antibacterial activity of quinolones is improved by modifications of different substituents in different positions. The color of the groups in the bracket correlates with the type of activities.

Fig. 3. The structure–pharmacokinetic relationship of quinolones. The pharmacokinetics of quinolones is improved by modifications of different substituents in different positions. The color of the groups correlates with the color of a pharmacokinetic property.

Fig. 4. The structure–toxicity relationship of quinolones. The toxicity of quinolones is altered by modifications of different substituents in different positions. The color of the groups in the bracket correlates with the type of toxicity.

Fig. 5. The structure of DNA gyrase and topoisomerase IV and human topoisomerase IIα. The GyrB and its equivalent domain on topoisomerase IV (ParE/GrlB) are responsible for hydrolyzing ATP during the cleavage/ligation process. The GyrA contains the tyrosine active site, which takes part in the breakage/reunion of the chromosomes. The CTD region, which is only observed in the GyrA but not in ParC/GrlA, is involved in topology recognition. Unlike two distinct domains seen in bacterial enzymes, the two subunits A and B of human topoisomerase IIα are fused together to form the homodimer enzyme.

Fig. 6. Intracellular action of quinolones. Quinolones bind to the DNA–enzyme cleavage complex at the cleavage-ligation active site. This binding creates a steady-state concentration of cleavage complexes and disrupts the replication process, which causes collision of the stabilized cleavage complexes with the DNA replication systems (replication fork, transcription complexes, and tracking systems) leading to chromosomal breaks (a). In response to this damage, SOS response and other DNA repair pathways are activated, resulting in subsequent action of the SOS system, such as extended cell filaments by expression of LexA repressor and programmed cell death by activation of toxin–antitoxin modules (b).

Fig. 7. A simplified diagram of the water–metal ion bridge between a fluoroquinolone and topoisomerase IV – DNA cleavage complex. Fluoroquinolone (black) binds via a non-catalytic Mg2+ ion (red) through four water molecules (blue) that fill out the coordination sphere of the Mg2+ ion, interacting with the side chains of the serine and acidic residues (yellow).

Fig. 8. The structure of novel quinolones and their C7 substituents. The varied C7 substituents are presented in orange.

Fig. 9. The pharmacophore structure of quinolones and quinazolinediones showing different potential binding sites.