ReviewTransferable mechanisms of quinolone resistance
Introduction
Nalidixic acid (NAL) was the first quinolone-derived agent demonstrating antibacterial activity as well as useful clinical parameters [1], being followed in the 1970s by novel compounds of this family such as pipemidic acid, although the clinical indication for these quinolones remained limited to urinary tract infections. The posterior addition of a fluorine atom at position 6 of the quinolone molecule greatly enhanced its activity. Since then, a large series of molecules of this family has been synthesised and several have been introduced into clinical practice, with ciprofloxacin (CIP) being the most representative [2]. However, some quinolones have been withdrawn from clinical practice following restriction of their use owing to secondary effects, including some deaths [3], [4], [5].
Fluoroquinolones (FQs) have been extensively used to treat a great variety of bacterial infections [6], [7], [8], [9]. Moreover, some FQs possess activity against eukaryotic targets and have been studied as a possible novel antiparasitic treatment [10], [11] or explored as potential antineoplastic agents [12]. Finally, quinolones have been extensively used in veterinary practice [13], [14]. However, the World Health Organization (WHO) currently considers FQs to be critically important antimicrobials, proposing very restricted use in veterinary practice [15], and a number of countries such as those of the European Union have forbidden some related uses (i.e. use as growth promoters).
This high level of use results in the selection and spread of quinolone-resistant microorganisms [13], [16], [17]. For a long time, the mechanisms of quinolone resistance described were exclusively chromosomal (Table 1), including specific amino acid substitutions in the quinolone targets (DNA gyrase and topoisomerase IV), decreased quinolone uptake into bacteria owing to either alterations in the outer membrane protein composition or to overexpression of efflux pumps, and alterations in the expression levels of the quinolone targets [18], [19]. None the less, the absence of transferable mechanisms of quinolone resistance (TMQRs) has long been of note and considered to be unlikely as quinolones are fully synthetic drugs [20].
Section snippets
The history of transferable mechanisms of quinolone resistance
Although the first definitively established TMQR was described in 1998 [21], various articles published prior to this year presented similar results [22], [23], [24]. However, these results were not confirmed, or further studies showed possible data misinterpretation.
In 1985, conjugation of NAL resistance was reported with a frequency of 10−6–10−7, but the transfer of a plasmid was not established and ethidium bromide was unable to revert the resistance in the transconjugants [24]. Then a
Quinolone target protection
During a study aimed at establishing the presence of extended-spectrum β-lactamases encoded on conjugative plasmids in Enterobacteriaceae, the transfer of a quinolone resistance determinant able to confer low-level resistance to some quinolones was detected [21]. This study also showed that strains carrying the aforementioned plasmid acquired quinolone resistance more easily [21].
Further studies identified the gene encoding the protein responsible for this phenomenon [49]. This gene was named
Concluding remarks
Currently, TMQRs are extensively described around the world. Although they usually result in only a slight increase in the MICs of quinolones, their effect is additive and their presence may facilitate the development of full quinolone resistance. Furthermore, possible specific substitutions may enhance their activity. The emergence of new related genes may continue in the next years, whilst the possible adaptation of other enzymes, similar to what occurred with AAC(6′)-Ib, is a potential risk.
Acknowledgments
The logistic support of Laura Puyol and Diana Barrios is acknowledged.
Funding: JR has a Miguel Servet Fellowship (Instituto de Salud Carlos III, Spain).
Competing interests: None declared.
Ethical approval: Not required.
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