39

Mechanisms of Action and of Resistance

to Quinolones
José L. Martínez
Departamento de Biotecnología Microbiana, Centro Nacional de Biotecnología, Consejo Superior de
Investigaciones Científicas, CSIC, Madrid, Spain

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

2.2 ­Mechanism of Action of Quinolones

Quinolones are a group of synthetic antibiotics obtained during chloroquine
synthesis, which were discovered more than five decades ago (Lesher et  al.
1962). The first member of the family, nalidixic acid, was soon introduced into
clinics, but just for treating urinary infections by Gram‐negative microorgan-
isms (Deitz et al. 1963). In the next decade there was a constant release into
clinics of novel quinolones such as the oxolinic acid. However the range of
infections for which these antimicrobial compounds were useful remained to
be quite limited. In the decade of the 1980s, a new generation of quinolones
that contain a fluorine and novel ring moieties (fluoroquinolones) was
­developed (Ball 2000). This second generation of quinolones presented better
pharmacological properties as well as a better entrance into Gram‐positive
microorganisms. Consequently, they were considered broad‐spectrum antibi-
otics. Among them, ciprofloxacin still remains as the antimicrobial of choice
not only for treating a variety of infections, mainly those by Gram‐negative
organisms, but also for treating Gram‐positive infections. A newer generation
of quinolones with improved pharmacological properties includes widely used
antimicrobials such as levofloxacin (Anderson and Perry 2008).
The targets of the quinolones are the bacterial topoisomerases DNA gyrase and
topoisomerase IV (Khodursky and Cozzarelli 1998; Shen et al. 1989). Both enzymes
comprise two different subunits that form a tetramer and play essential roles in
most processes of the DNA activity, including replication, transcription, recombi-
nation, and repair. While gyrase is the main responsible for modulating DNA
supercoiling and removing the torsional stress associated with DNA replication
and transcription, the role of topoisomerase IV in these processes is less relevant,
being mainly involved in removing knots that accumulate in bacterial DNA as a
result of different processes as well as in decatenating daughter chromosomes after
replication (Champoux 2001; Levine et al. 1998). To perform their functions, bac-
terial topoisomerases generate double‐strand breaks in the bacterial DNA. In such
a way, while topoisomerases ara essential for microbial life, their uncontrolled
activity may cause fragmentation of the bacterial genome. Quinolones act by
increasing the concentration of DNA–enzyme cleavage complexes and inhibit
DNA ligation, hence increasing DNA breaks and stalling the replication fork pro-
gression (Anderson and Osheroff 2001). Thus, these antimicrobials have been
dubbed as “topoisomerase poisons” because they convert these two enzymes into
intracellular toxins (Kreuzer and Cozzarelli 1979).
It is worth mentioning that due to this mechanism of action that leads to
DNA damage, quinolones induce SOS response and increase recombination
and mutagenesis (Lopez et al. 2007; Lopez and Blazquez 2009; Phillips et al.
1987; Ysern et al. 1990). Therefore quinolones have been considered as pro-
moters of genetic variation (Blazquez et  al. 2012), including those processes
leading to antibiotic resistance.
 2.3  Mutations in the Genes Encoding the Targets of Quinolones 41

2.3 ­Mutations in the Genes Encoding the Targets

of Quinolones
Although, as above stated, different quinolone resistance genes have been
described, mutations in the genes encoding the targets of these antimicrobials
still remain as the most prevalent cause for the acquisition of high‐level resist-
ance to quinolones (Jacoby 2005). Notably the main target of quinolones is dif-
ferent in Gram‐negative (gyrase) and in Gram‐positive (topoisomerase IV)
organisms (Drlica and Zhao 1997; Ferrero et al. 1994). In agreement with this
situation, mutations in the genes encoding the two subunits of the bacterial
gyrase, gyrA and gyrB (mainly in gyrA), are the most relevant in Gram‐negative
resistant bacteria, whereas Gram‐positive microorganisms most frequently
present mutations in the genes parC and parE (mainly in parC), encoding the
subunits of the bacterial topoisomerase IV. The analysis of quinolone‐resistant
mutants from different organisms have shown that there are hot spots within
gyrA and parC, dubbed as quinolone resistance‐determining region (QRDR),
where most mutations accumulate (Piddock 1999). The amino acids more rel-
evant for acquiring resistance, based on the Escherichia coli sequences of the
topoisomerases, are serine 83 and aspartate 87 for GyrA and serine 79 and
aspartate 83 for ParC. These mutants present a reduced quinolone–enzyme
binding affinity, without reducing the cleavage activity of the topoisomerase in
the absence of the antibiotic. While these mutants can present fitness costs on
occasions (Redgrave et al. 2014), there are some examples showing that, at least
for some mutations, a substantial fitness cost is not observed (Balsalobre and de
la Campa 2008), or the cost associated with resistance depends on the genomic
context of the strain that has acquired quinolone resistance (Luo et al. 2005).
In addition, it has been shown that even in the case of mutations in the topoi-
somerases producing a relevant fitness cost, compensatory mutations that
alleviate such cost can be selected. Notably, some of these compensatory muta-
tions occur in other elements as regulators of efflux pumps or a different topoi-
somerase (or topoisomerase subunit), which are of relevance for the acquisition
of quinolone resistance (Andersson and Hughes 2010). Consequently, in some
of these cases, compensation of fitness costs is associated with an increased level
of resistance to quinolones. This is the situation of E. coli, an organism in which
a combination of different mutations leading to high‐level quinolone resistance
is not an infrequent event. In this bacterium, a gyrA mutant presenting the
S83L and D87N double substitution displays a ciprofloxacin minimal inhibi-
tory concentration (MIC) of 0.38 μg ml−1, with a 3% reduction in fitness as
compared with the wild‐type strain. The acquisition of a S80I mutation in ParC
increases MIC to 32 μg ml−1, and the fitness of this strain presenting mutations
in both topoisomerases is 1% higher than the wild‐type strain (Marcusson et al.
2009). These results indicate that the accumulation of quinolone resistance muta-
tions does not necessarily produce a higher burden to the resistant microorganism.
42 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.

2.4 ­Multidrug Efflux Pumps and Quinolone

Resistance
The discovery of multidrug resistance (MDR) efflux pumps and the analysis of
the substrates they can extrude challenged the ideas that mutations in the
genes encoding the targets of these antimicrobials would be the unique cause
of quinolone resistance. Indeed bacterial MDR efflux pumps can extrude qui-
nolone. Even more, despite their synthetic origin, quinolones are among the
most usual substrates of these pumps (Hooper 1999).
MDR efflux pumps are encoded in the core genomes of all bacterial species
(Alonso et al. 1999; Li and Nikaido 2009; Nikaido and Takatsuka 2009; Piddock
2006a; Saier et al. 1998), and they contribute to intrinsic and acquired resist-
ance to different antibiotics, including quinolones (Fernández 2012; Garcia‐
Leon et al. 2014a; Hernando‐Amado et al. 2016; Li et al. 2015; Martinez et al.
2009; Piddock 2006a; Poole 2007; Vila and Martínez 2008). The ubiquitous
presence of these elements in all living cells together with their high conserva-
tion suggests that they are ancient elements in bacterial genomes, which
evolved long before the wide use of antibiotics for treating infections, and that
they likely present functions with relevance for the bacterial physiology
besides antibiotic resistance (Alvarez‐Ortega et  al. 2013; Blanco et  al. 2016;
Fetar et al. 2011; García‐León et al. 2014b; Martinez et al. 2009; Piddock 2006b;
Poole 2012).
Until now five different families of MDR efflux pumps have been described
(Hernando‐Amado et  al. 2016), and four of these five families of MDR
­systems  –  the ATP‐binding cassette (ABC) family, the major facilitator
superfamily (MFS), the resistance‐nodulation‐division (RND) family, and the
multidrug and toxic compound extrusion (MATE) family – may participate
in quinolone resistance (Poole 2000a, b). Although in a few cases such as NorC
in Staphylococcus aureus (Truong‐Bolduc et al. 2006) or Rv1634 in Mycobacterium
tuberculosis (De Rossi et al. 2002) quinolones seem to be the unique (or at least
the predominant) antibiotics extruded by these resistance determinants, efflux
pumps usually present little selectivity in the sense that one single efflux pump
can extrude a variety of different substrates (Martinez et al. 2009).
The expression of MDR efflux pumps is tightly controlled by local and
global regulators; they are usually expressed at low level under regular growing
conditions in the laboratory (Grkovic et al. 2002). The basal level of expression
 2.5  Transferable Quinolone Resistance 43

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).

2.5 ­Transferable Quinolone Resistance

The above described mechanisms are based on the selection of mutants. For
them, resistance can spread just by clonal expansion. Nevertheless, the possi-
bility of transferrable mechanisms of resistance to quinolones was firstly pro-
posed in the basis of in vitro analysis (Gomez‐Gomez and Blazquez 1997;
Martinez et  al. 1998), and plasmids carrying quinolone resistance genes
(dubbed qnr) were described soon afterwards (Martinez‐Martinez et al. 1998).
Qnr is a member of the pentapeptide repeat protein (PRP) family (Vetting et al.
2006). It binds the bacterial topoisomerases (DNA gyrase and topoisomerase IV)
protecting them from the activity of quinolones. Five qnr families, namely,
44 2  Mechanisms of Action and of Resistance to Quinolones

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

might contain other resistance determinants, being particularly relevant the

association of qnr genes with genes coding for extended‐spectrum ß‐lactamases
and AmpC ß‐lactamases (Strahilevitz et al. 2009). These co‐resistance associa-
tions, in addition to the presence of other resistance genes in qnr‐encoding
plasmids, have likely favored the dissemination of qnr genes even when
quinolones are not used for therapy.
Although less prevalent at the moment, other transferrable mechanisms of
quinolone resistance besides Qnr proteins have been described. Among them,
two quinolone efflux pumps, QepA (Yamane et al. 2007) and OqxAB (Hansen
et  al. 2004, 2007), have been found to be encoded in different plasmids. In
addition to quinolones, QepA extrudes a narrow range of substrates, including
erythromycin, ethidium bromide, and acriflavine. OqxAB (almost exclusively
present in organisms causing animal infections) however presents a wider sub-
strate range that includes tetracycline, chloramphenicol, benzalkonium chlo-
ride, and triclosan (Hansen et al. 2007).
A quinolone‐inactivating enzyme (ciprofloxacin and norfloxacin),
encoded by the aac(6′)‐Ib‐cr gene, has been described more than 10 years
ago. This enzyme evolved toward quinolone resistance from an original
aminoglycoside acetyltransferase through the acquisition of two amino acid
changes (Trp102Arg and Asp179Tyr) (Robicsek et al. 2006), which allow the
inactivation of quinolones at the cost of reducing the efficacy of the enzyme
against aminoglycosides (Robicsek et al. 2006). This modification strongly
suggests that the new evolved enzyme has been selected under strong qui-
nolone selective pressure, likely during antimicrobial treatment. Since asso-
ciation of aac(6′)‐Ib‐cr with genes encoding the ß‐lactamase CTX‐M‐15 or
extended‐spectrum ß‐lactamases has been reported (Coque et  al. 2008;
Pitout et  al. 2008), co‐selection of this determinant by other antibiotics
besides quinolones is a suitable possibility.
It has been stated that the risk for the dissemination of resistance is lower
in the case of mutations than in the case of HGT‐acquired genes. For the
first, spread is achieved through clonal expansion, whereas for the second
both clonal expansion and gene transfer are both at work. While this is the
most common rule, there are some exceptions, and one of them consists in
antibiotic resistance mutations in genes encoding bacterial topoisomerases.
Indeed, it was described that parC and gyrA mutations, and the associated
phenotype of resistance to quinolones, can be transferred by transformation
in Streptococcus pneumoniae clinical isolates (Ferrandiz et al. 2000). Further,
mutation‐acquired resistance to quinolones can be transferred from the
­viridans group streptococci to S. pneumoniae (Balsalobre et al. 2003), indi-
cating that commensal bacteria might contribute by means of transferring
target mutations to the development of quinolone resistance, at least in the
case of S. pneumoniae.
46 2  Mechanisms of Action and of Resistance to Quinolones

2.6  ­Stenotrophomonas maltophilia and Its Uncommon

Mechanisms of Resistance to Quinolones
As above stated, the selection of mutations in genes encoding the bacterial
topoisomerases still remains as the main mechanism of resistance to quinolo-
nes. Nevertheless the Gram‐negative opportunistic pathogen S. maltophilia is
an exception to such rule. Studies with in vitro obtained quinolone‐resistant
mutants as well as with clinical isolates have shown that quinolone resistance
is not associated with mutations in bacterial topoisomerases (Garcia‐Leon
et al. 2014a; Ribera et al. 2002; Valdezate et al. 2002). Some recent works have
described the presence of amino acid changes in the topoisomerases of clinical
S. maltophilia isolates, but the observed changes are outside the QRDRs and
seem to be likely allelic forms of these genes more than mutations involved in
quinolone resistance (Cha et al. 2016; Jia et al. 2015).
The analysis of quinolone‐resistant mutants and clinical isolates of S. maltophilia
has shown that the MDR efflux pump SmeDEF is a major contributor to the
intrinsic resistance to quinolones of this microorganism when expressed at its
basal wild‐type level (Zhang et al. 2001). Overexpression of this efflux pump
increase MIC levels of quinolones above the breakpoints defining resistance in
this microorganism (Alonso and Martinez 2000; Sanchez et al. 2002; Sanchez
and Moreno 2005), and mutants overexpressing SmeDEF are frequently found
among clinical S. maltophilia isolates (Alonso and Martinez 2001; Cho et al.
2012; Gould and Avison 2006; Liaw et  al. 2010; Sanchez et  al. 2004). While
overexpression of this efflux pump produces a fitness cost (Alonso et al. 2004),
it might be possible that this cost might be lower than those associated with
mutations in genes encoding the bacterial topoisomerases. This differential fit-
ness might be the reason for the lack of topoisomerase mutants among the
quinolone‐resistant mutants of this bacterial species. Notably, even when the
SmeDEF efflux pump is removed, mutations in topoisomerases are not selected
in presence of quinolones. The main mechanism of resistance in this case
becomes to be the overexpression of another efflux pump, SmeVWX (Garcia‐
Leon et al. 2014a). Overexpression of this efflux pump has been reported for
clinical S. maltophilia isolates, indicating that these types of mutants are
selected in vivo (Garcia‐Leon 2015).
In addition to efflux pumps capable of efficiently extruding quinolones, S.
maltophilia presents in its genome (Sanchez et al. 2008; Shimizu et al. 2008) a
qnr determinant (Smqnr) that contributes to intrinsic resistance to these anti-
microbials (García‐León et al. 2012; Sanchez and Martinez 2010; Sanchez and
Martinez 2015b). Nevertheless, Smqnr mutants have not been described nei-
ther upon in vitro selection by quinolones nor in clinical isolates, which cast
doubts on the role of this determinant in acquired resistance to quinolones of
S. maltophilia. More recently, a novel mechanism of resistance based on the
increased expression of the heat shock response upon the inactivation of
 ­  References 47

RNase G has been described in S. maltophilia (Bernardini et al. 2015). However,

although it has been proposed that the responses to stress are relevant players
in the development of antibiotic resistance among bacterial pathogens (Poole
2012), the clinical significance of this mechanism of resistance remains to be
fully established.
One important aspect concerning quinolone resistance in S. maltophilia is
the way it can impact resistance to other drugs. The mutations in the genes
encoding bacterial topoisomerases, which are regularly found in quinolone‐
resistant bacteria, do not alter the susceptibility to other antibiotics of such
mutants. However, the increased expression of efflux pumps can simultane-
ously alter the susceptibility to several different antibiotics. Stenotrophomonas
maltophilia is an organism with a characteristic low level of susceptibility to
antibiotics (Sanchez et  al. 2009). The combination trimethoprim/sulfameth-
oxazole is sometimes the last resort of antimicrobial therapy of infections
caused by this pathogen. It has been described that the efflux pump SmeDEF,
in addition to being a main player in the acquisition of resistance to quinolo-
nes, is also involved in trimethoprim/sulfamethoxazole resistance (Sanchez
and Martinez 2015a).

­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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