Action and Resistance of Quinolones
Action and Resistance of Quinolones
2.1 Introduction
The first rationally developed antibiotics had synthetic origin (Domagk 1935;
Horlein 1936). However, the explosive development of new antibiotics came
from the search of natural compounds produced by environmental microorgan-
isms (Waksman and Woodruff 1940). Soon after the introduction of antibiotics
for therapy, resistant variants of the microorganisms began to be selected under
the selective pressure of the treatment. Two were (and are still now) the genetic
causes of this resistance, mutation and acquisition of resistance determinants by
means of horizontal gene transfer (HGT). Antibiotic‐producing microorganisms
require to encode in their genome resistance determinants in order to avoid the
activity of the antimicrobials that they produce. Consequently, it was proposed
and later on widely accepted that resistance genes acquired through HGT by
human pathogens were originated in the antibiotic‐producing organisms
(Benveniste and Davies 1973; Davies 1994; Webb and Davies 1993). In line with
these thoughts and since quinolones are purely synthetic drugs, not present in
nature before their synthesis, it was thought that quinolone resistance genes
would not exist in nature, and consequently the only mechanisms leading to qui-
nolone resistance should be mutations in the genes encoding their topoisomer-
ase targets (Crumplin and Odell 1987) or the transporters of these antimicrobials
(Piddock 1999). Nowadays we know that this viewpoint was oversimplistic and
different genes, some of which are plasmid encoded, are involved in the acquisi-
tion of quinolone resistance by bacterial pathogens. Along with the current
chapter, we will review updated information on the mechanisms and the genetic
basis of quinolone resistance among virulent microorganisms.
Antibiotic Drug Resistance, First Edition. Edited by José‐Luis Capelo‐Martı ́nez and Gilberto Igrejas.
© 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.
40 2 Mechanisms of Action and of Resistance to Quinolones
Rather, increase in resistance may correlate with a higher fitness of the mutant
strain. Whether or not this type of compensatory mutations can be selected in
the absence of selection remains to be fully elucidated. However this situation
could be a good example of the potential selection of antibiotic‐resistant
mutants even in the absence of antibiotics.
varies depending on the efflux pump. In this regard, some efflux pumps p resent
an expression level enough for contributing to intrinsic resistance to quinolo-
nes (Li et al. 1994; Vila and Martinez 2008), whereas for others, presenting
lower level of expression, such contribution is minimal if any. In any case one
important consequence of these studies is that inhibitors of efflux pumps may
improve the activity of quinolones (Renau et al. 1999).
Expression of efflux pumps can be triggered in the presence of an effector or
under some specific growing conditions (García‐León et al. 2014b; Hernandez
et al. 2011; Rosenberg et al. 2003). In addition, mutants presenting high dere-
pressed levels of expression of efflux pumps can be selected in the presence of
antibiotics, both in vitro and in vivo. These mutants can present reduced sus-
ceptibility to quinolones and to other antibiotics (acquired resistance) (Alonso
and Martinez 2001; Cohen et al. 1989; Jalal et al. 2000; Ziha‐Zarifi et al. 1999),
although in several occasions (with some exceptions such as Stenotrophomonas
maltophilia; see below) the observed MICs are below the breakpoint levels
used for defining clinical resistance (Martinez et al. 2015) and high‐level resistance
is achieved just in combination with other mutations (Marcusson et al. 2009).
In occasions, high‐level quinolone resistance can be achieved upon the
simultaneous expression of some different MDR efflux pumps (Yang et al.
2003). However, in most studied cases, the highest level of resistance to qui-
nolones is achieved when mutations in the target genes and increased efflux
occur simultaneously (Llanes et al. 2006).
As above stated, MDR efflux pumps present a wide range of substrates,
which include antibiotics belonging to different structural families (Paulsen
2003). This means that the overexpression of one single efflux pump increases
the MICs for a variety of antibiotics. Consequently, efflux pumps overexpress-
ing mutants can be selected by the selective pressure of any of the substrates of
the pump. In other words, selective pressure by one antibiotic can also select
for quinolone resistance (cross‐selection) if both antimicrobials are substrates
of the efflux pump (Cohen et al. 1989).
qnrA, qnrB, qnrS, qnrC, and qnrD (Cavaco et al. 2009; Hata et al. 2005; Jacoby
et al. 2006; Strahilevitz et al. 2007; Tran and Jacoby 2002; Wang et al. 2009),
have been so far described in plasmids disseminated among bacterial pathogens.
Other members of the PRP family besides Qnr, such as MfpA that contributes
to the intrinsic resistance of Mycobacterium to quinolones (Montero et al.
2001), might be relevant for resistance to these antimicrobials.
It is important to be noticed that qnr genes have been found to be present
in the chromosomes of environmental bacteria, mainly in water‐dwelling
microorganisms (Arsene and Leclercq 2007; Rodriguez‐Martinez et al. 2008;
Sanchez et al. 2008). Indeed, it has been clearly demonstrated that Shewanella
algae is the origin of plasmid‐encoded qnrA genes (Poirel et al. 2005b), and it
has been proposed, although the evidence is not so clear, that Vibrionaceae
might be a reservoir for other plasmid‐encoded qnr genes (Cattoir et al. 2007;
Poirel et al. 2005a).
Quinolones have been (and are still in some countries) largely used in fish
farms without major concerns about the associated risks for human health
until recently (Baquero et al. 2008; Cabello 2006). The reasoning behind was
that mutation‐driven resistance will select resistant mutants in bacteria infect-
ing (or colonizing) fishes as well as in the inhabitants of water and sludge; none
of them will be of relevance as a human pathogen. Since antibiotic resistance
due to mutation is not usually transferrable (see below), the clonal expansion of
these resistance microorganism will not impact on the potential acquisition of
resistance by human pathogens. Nevertheless, once the possibility of the
acquisition of quinolone resistance through HGT has been demonstrated,
the possibility that the intense quinolone selective pressure in aquaculture
(Baquero et al. 2008; Cabello 2006; Martinez 2008, 2009) is likely favoring the
selection and spread of their resistance elements must be taken into considera-
tion. A very first step in this process can be the transfer of a qnr gene from its
original host to a mobile genetic element present in an environmental micro-
organism (Martinez 2008). This could be the case of the qnrS2 gene, found on
the same broad‐host‐range IncU‐type plasmid from two different Aeromonas
isolates from two non‐connected geographical locations (Cattoir et al. 2008;
Picao et al. 2008).
It is worth mentioning that although qnr genes have been found in a large
range of plasmids (Strahilevitz et al. 2009), the modules involved in their trans-
mission present some common characteristics. qnrA and qnrB are usually
located in sul1‐type integrons, which usually harbor other antibiotic resistance
genes, including ß‐lactamases and aminoglycoside‐inactivating enzymes (Wang
et al. 2003) and are associated with ISCR1 (Garnier et al. 2006; Nordmann and
Poirel 2005). qnrS genes are not harbored by integrons; however they are fre-
quently associated with the TEM‐1 ß‐lactamase‐containing Tn3 transposon
(Hata et al. 2005; Strahilevitz et al. 2009). Finally, the plasmids themselves
2.5 Transferable Quinolone Resistance 45
Acknowledgments
Work in the laboratory is supported by was supported by Instituto de Salud
Carlos III (grant RD16/0016/0011)—cofinanced by the European Development
Regional Fund “A Way to Achieve Europe,” by grant S2017/BMD‐3691
InGEMICS‐CM, funded by Comunidad de Madrid (Spain) and European
Structural and Investment Funds and by the Spanish Ministry of Economy and
Competitivity (BIO2017‐83128‐R).
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