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Edited by: In this review an overview is given on antibiotic resistance (AR) mechanisms with special
Timothy Rutland Walsh, Cardiff
attentions to the AR genes described so far preceded by a short introduction on the dis-
University, UK
covery and mode of action of the different classes of antibiotics. As this review is only
Reviewed by:
M. Pilar Francino, Center for Public dealing with acquired resistance, attention is also paid to mobile genetic elements such as
Health Research, Spain plasmids, transposons, and integrons, which are associated with AR genes, and involved
Jun Liu, Mount Sinai School of in the dispersal of antimicrobial determinants between different bacteria.
Medicine, USA
Keywords: antimicrobial resistance mechanisms, acquired, antibiotics, mobile genetic elements
*Correspondence:
Henk J. M. Aarts, National Institute of
Public Health and the Environment,
Antonie van Leeuwenhoekla 9, 3721
MA Bilthoven, Utrecht, Netherlands.
e-mail: henk.aarts@rivm.nl
These AR phenotypes can be achieved in microorganisms by chro- Decreased permeability (Hancock, 1981; Taber et al., 1987), (III)
mosomal DNA mutations, which alter existing bacterial proteins, Ribosome alteration (Poehlsgaard and Douthwaite, 2005), (IV)
through transformation which can create mosaic proteins and/or Inactivation of the drugs by aminoglycoside-modifying enzymes
as a result of transfer and acquisition of new genetic material (Shaw et al., 1993). Intrinsic mechanisms, i.e., efux pumps and
between bacteria of the same or different species or genera (Spratt, 16S rRNA methylases but also chromosomal mutations can cause
1994; Maiden, 1998; Ochman et al., 2000). the rst three resistance properties. In recent years acquired 16S
There are numerous examples of mutation based resistance. rRNA methylases appear to have increased in importance (Gali-
For example, macrolide resistance can be due to nucleotide(s) base mand et al., 2005; Doi and Arakawa, 2007; Table 1). The rst gene
substitutions in the 23S rRNA gene. However, a similar resistance identied of a plasmid-mediated type of aminoglycoside resistance
phenotype may also result from mutations within the riboso- was armA (Galimand et al., 2003). To date ve additional methy-
mal proteins L4 and L22 (Vester and Douthwaite, 2001). Single lases have been reported, i.e., npmA, rmtA, rmtB, rmtC, and rmtD
nucleotide polymorphisms (SNPs) can be the cause for resis- (Courvalin, 2008; Doi et al., 2008). Data regarding the 16S rRNA
tance against the synthetic drugs quinolones, sulfonamides, and methylase genes are accumulated and provided at the website:
trimethoprim (Huovinen et al., 1995; Hooper, 2000; Ruiz, 2003) www.nih.go.jp/niid/16s_database/index.html.
and mutations within the rpsL gene, which encodes the riboso- The major encountered aminoglycoside resistance mechanism
mal protein S12, can result in a high-level streptomycin resistance is the modication of enzymes. These proteins are classied into
(Nair et al., 1993). A frame shift mutation in the chromosomal three major classes according to the type of modication: AAC
ddl gene, encoding a cytoplasm enzyme d-Alad-Ala ligase, can (acetyltransferases), ANT (nucleotidyltransferases or adenyltrans-
account for glycopeptides resistance (Casadewall and Courvalin, ferases), APH (phosphotransferases; Shaw et al., 1993; Wright and
1999). Thompson, 1999; Magnet and Blanchard, 2005; Wright, 2005;
Ramirez and Tolmansky, 2010). Within these classes, an additional
ACQUIRED RESISTANCE subdivision can be made based on the enzymes different region
This review deals with the description of acquired resistance specicities for aminoglycoside modications: i.e., there are four
against several classes of antibiotics. For each class the develop- acetyltransferases: AAC(1), AAC(2 ), AAC(3), and AAC(6 ); ve
ment of resistance is summarized along with the mechanisms nucleotidyltransferases: ANT(2 ), ANT(3 ), ANT(4 ), ANT(6),
of action. Furthermore an extensive summary is given of the and ANT(9) and seven phosphotransferases: APH(2 ), APH(3 ),
resistance mechanisms and resistance genes involved. APH(3 ), APH(4), APH(6), APH(7 ), and APH(9). Furthermore,
there also exists a bifunctional enzyme, AAC(6 )APH(2 ), that
AMINOGLYCOSIDE can acetylate and phosphorylate its substrates sequentially (Shaw
History and action mechanism et al., 1993; Kotra et al., 2000). Table 1 displays the currently known
The aminoglycoside antibiotics initially known as aminoglyco- aminoglycoside resistance genes. The action mechanisms of the
sidic aminocyclitols are over 60 years old (Siegenthaler et al., 1986; determinants, the variety in gene lengths, accession numbers, and
Begg and Barclay, 1995). In the early 1940s the rst amino- the distribution are all indicated. As can be deduced from the sec-
glycoside discovered was streptomycin in Streptomyces griseus ond column of Table 1, inconsistencies arose in the nomenclature
(Schatz and Waksman, 1944). Several years later, additional amino- of genes for aminoglycoside-modifying enzymes (Vakulenko and
glycosides were characterized from other Streptomyces species; Mobashery, 2003). In some cases, genes were named according
neomycin and kanamycin in 1949 and 1957, respectively. Further- to the site of modication, followed by a number to distinguish
more, in the 1960s gentamicin was recovered from the actino- between genes. Using a different nomenclature, for example, the
mycete Micromonospora purpurea. Because most aminoglycosides genes for AAC(6 )-Ia and AAC(3)-Ia are referred to as aacA1 and
have been isolated from either Streptomyces or Micromonospora aacC1, respectively. The nomenclature proposed by Shaw et al.
a nomenclature system has been set up based on their source. (1993), who utilize the identical names for the enzymes and the
Aminoglycosides that are derived from bacteria of the Streptomyces corresponding genes, but the names of genes are in lowercase
genus are named with the sufx -mycin, while those which are letters and italicized will be used in this review (see Table 1).
derived from Micromonospora are named with the sufx -micin. According to this more convenient nomenclature, the genes for
The rst semi-synthetic derivatives were isolated in the 1970s. the AAC(6 )-Ia and AAC(3)-Ia enzymes are termed aac(6 )-Ia and
For example netilmicin is a derivative of sisomicin whereas aac(3)-Ia, respectively.
amikacin is derived from kanamycin (Begg and Barclay, 1995;
Davies and Wright, 1997). -LACTAM
Aminoglycosides are antimicrobials since they inhibit protein History and action mechanism
synthesis and/or alter the integrity of bacterial cell membranes As already mentioned before, the rst antibiotic discovered was a -
(Vakulenko and Mobashery, 2003). They have a broad antimicro- lactam, i.e., penicillin. The Scottish scientist Alexander Flemming
bial spectrum. Furthermore, they often act in synergy with other accidentally noticed the production of a substance with antimi-
antibiotics as such it makes them valuable as anti-infectants. crobial properties by the mold Penicillium notatum (Flemming,
1929). Over the last 30 years, many new -lactam antibiotics have
Resistance mechanisms been developed. By denition, all -lactam antibiotics have a -
Several aminoglycoside resistance mechanisms have been recog- lactam nucleus in their molecular structure. The -lactam antibi-
nized; (I) Active efux (Moore et al., 1999; Magnet et al., 2001), (II) otic family includes penicillins and derivatives, cephalosporins,
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van Hoek et al. Acquired antibiotic resistance genes
(Continued)
Table 1 | Continued
(Continued)
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van Hoek et al. Acquired antibiotic resistance genes
Table 1 | Continued
(Continued)
Table 1 | Continued
This table was adapted from: Elbourne and Hall (2006), Magnet and Blanchard (2005), Partridge et al. (2009), Ramirez and Tolmansky (2010), Shaw et al. (1993),
Vakulenko and Mobashery (2003), and data provided by B. Guerra, B. Aranda, D. Avsaroglu, B. Ruiz del Castillo, and R. Helmuth, on behalf of the Med-Vet Net (EU
Network of Excellence) WP29 Project Group. The data were collected within the subproject AMEs, with following participants representing their Institutions: Agnes
Perry Guyomard (ANSES), Dik Mevius (CVI), Yvonne Agerso (DTU), Katie Hopkins (HPA), Silvia Herrera (ISCIII), Alessandra Carattoli (ISS), Antonio Battisti (IZS-Rome),
Stefano Lollai (IZS-Sardegna), Lotte Jacobsen (SSI), Bla Nagy (VMRI), M. Rosario Rodicio and M. C. Mendoza (University of Oviedo, UO), Luis Martnez-Martnez
(University Hospital of Valdecilla, HUV), and Bruno Gonzalez-Zorn (UCM).
ACT, Acetyltransferase; MET, Methyltransferase; NUT, Nucleotidyltransferase; PHT, Phosphotransferase.
A
Although the sat genes are not aminoglycoside resistance determinants, they encode streptothricin acetyltransferases, for convenience they are included in this
table.
carbapenems, monobactams, and -lactam inhibitors (Williams, generation antimicrobials have improved Gram-negative and vari-
1987; Bush, 1989; Petri, 2006; Queenan and Bush, 2007). able Gram-positive activity; forth generation -lactams have good
The core compound of penicillin, 6-aminopenicillanic acid true broad spectrum activity against both Gram-negatives and
(6-APA) is used as the main starting point for the prepa- Gram-positives (Williams, 1987; Marshall et al., 2006). The sec-
ration of numerous semi-synthetic derivatives. Although the ond generation cephamycins are sometimes also grouped among
cephalosporins are often thought of as new and improved deriv- the cephalosporins.
atives of penicillin, they were actually discovered as naturally Because carbapenems diffuse easily in bacteria they are
occurring substances (Petri, 2006). They can be grouped in rst, considered as broad spectrum -lactam antibiotic. Imipenem
second, third, and forth generation cephalosporins according and meropenem are well known representative. Even though
to their spectrum of activity and timing of the agents intro- monobactams do not contain a nucleus with a fused ring attached,
duction. In general, rst generation agents have good Gram- they still belong to the -lactam antibiotics. The -lactamase
positive activity and relatively modest coverage for Gram-negative inhibitors, like clavulanic acid, do contain the -lactam ring,
organisms; second generation cephalosporins have increased but they exhibit negligible antimicrobial activity and are used in
Gram-negative and somewhat less Gram-positive activity; third combination with -lactam antibiotics to overcome resistance in
Frontiers in Microbiology | Antimicrobials, Resistance and Chemotherapy September 2011 | Volume 2 | Article 203 | 6
van Hoek et al. Acquired antibiotic resistance genes
bacteria that secrete -lactamase, which otherwise inactivates most -lactamase, TEM-1, was described in the early 1960s in Gram-
penicillins. negatives (Datta and Kontomichalou, 1965). Currently over 1,150
The -lactam antibiotics work by inhibiting the cell wall syn- chromosomal, plasmid, and transposon located -lactamases are
thesis by binding to so-called penicillin-binding proteins (PBPs) currently known (Bush and Jacoby, 2010; Drawz and Bonomo,
in bacteria and interfering with the structural cross linking of pep- 2010; Table 2).
tidoglycans and as such preventing terminal transpeptidation in Based on their activity to hydrolyze a small number or a vari-
the bacterial cell wall. As a consequence it weakens the cell wall ety of -lactams the enzymes can be subdivided into narrow-,
of the bacterium and nally results in cytolysis or death due to moderate-, broad-, and ESBLs. A commonly used denition spec-
osmotic pressure (Kotra and Mobashery, 1998; Andes and Craig, ies that broad spectrum -lactamases are capable to provide
2005). resistance to the penicillins and cephalosporins and are not inhib-
The -lactamase inhibitors can be classied as either reversible ited by inhibitors such as clavulanic acid and tazobactam. The
or irreversible and the latter are considered more effective in ESBLs confer resistance to the penicillins, rst-, second-, and
that they eventually result in the destruction of enzymatic activ- third-generation cephalosporins and aztreonam, but not to car-
ity. Not surprisingly the inhibitors in clinical use, i.e., clavulanic bapenems and are inhibited by -lactamase inhibitors. In recent
acid, sulbactam, and tazobactam are all examples of irreversible years acquired AR genes encoding ESBLs have become a major
-lactamase inhibitors (Bush, 1988; Drawz and Bonomo, 2010). concern (Bradford, 2001). In time the parent enzymes bla TEM-1 ,
bla TEM-2 , and bla SHV-1 have undergone amino acid substitutions
Resistance mechanisms (point mutations) evolving to the ESBLs, starting with bla TEM-3
The rst bacterial enzyme reported to destroy penicillin was an and bla SHV-2 (Bradford, 2001). Additional mutations at critical
AmpC -lactamase of E. coli (Abraham and Chain, 1940). Nowa- amino acids important for catalysis resulted in over 140 cur-
days, bacterial resistance against -lactam antibiotics is increas- rently known SHV and TEM ESBL variants. In addition, plasmid-
ing at a signicant rate and has become a common problem. encoded class C -lactamases or AmpC determinants, like bla CMY
There are several mechanisms of antimicrobial resistance to - have also caught peoples awareness (Jacoby, 2009). Furthermore,
lactam antibiotics. The most common and important mechanism in the past decade CTX-M enzymes have become very prevalent
through which bacteria can become resistant against -lactams ESBLs, both in nosocomial and in community settings (Cantn
is by expressing -lactamases, for example extended-spectrum and Coque, 2006).
-lactamases (ESBLs), plasmid-mediated AmpC enzymes, and Table 2 illustrates the size and diversity of the group of -
carbapenem-hydrolyzing -lactamases (carbapenemases; Brad- lactamases and ESBLs. The vast and still increasing number of
ford, 2001; Jacoby and Munoz-Price, 2005; Paterson and Bonomo, (broad spectrum) -lactamases and ESBLs has become a problem
2005; Poirel et al., 2007; Queenan and Bush, 2007; Jacoby, 2009). for the nomenclature for novel genes. Names have been assigned
The -lactamase family has been subdivided either based on according to individual preference rather than according to sys-
functionality or molecular characteristics. Initially, before genes tematic procedures (Bush, 1989). Fortunately, an authoritative
were routinely sequenced various biochemical parameters were website has been constructed on the nomenclature of ESBLs hosted
determined of the different -lactamases which allowed classica- by Jacoby and Bush1 .
tion of this AR determinants family into four groups (Bush et al.,
1995; Wright, 2005). Groups 1, 2, and 4 are serine--lactamases, CHLORAMPHENICOL
while members of group 3 are metallo--lactamases. Classication History and action mechanism
based on molecular characteristics, i.e., amino acid homology has In 1947, the rst chloramphenicol, originally referred to as
also resulted in four major groups, the so-called Ambler classes chloromycetin, was isolated from Streptomyces venezuelae (Ehrlich
AD, which correlate well with the functional scheme but lack et al., 1947). Probably because chloramphenicol is a molecule
details concerning the enzymatic activity. Ambler classes A, C, with a rather simple structure only a small number of syn-
and D include the -lactamases with serine at their active site, thetic derivates have been synthesized without adverse effects on
whereas Ambler class B -lactamases are all metallo-enzymes antimicrobial activity (Schwarz et al., 2004). In azidamfenicol two
who require zinc as a metal cofactor for their catalytic activi- chlorine atoms (Cl2 ) are replaced by an azide group. Substi-
ties (Ambler, 1980; Bradford, 2001; Paterson and Bonomo, 2005; tution of the nitro group (NO2 ), by a methylsulfonyl residue
Wright, 2005; Poirel et al., 2007, 2010; Bush and Jacoby, 2010; (SO2 CH3 ) resulted in the synthesis of thiamphenicol, whereas in
Drawz and Bonomo, 2010). In this review the Ambler classication the uorinated thiamphenicol derivative orfenicol the hydroxyl
will be used (Table 2). group (OH) is replaced with uorine (F).
In addition to the production of -lactamases resistance can Chloramphenicol is a highly specic and potent inhibitor
also be due to possession of altered PBPs. Since -lactams cannot of protein synthesis through its afnity for the peptidyltrans-
bind as effectively to these altered PBPs, the antibiotic is less effec- ferase of the 50S ribosomal subunit of 70S ribosomes (Schwarz
tive at disrupting cell wall synthesis. The PBPs are thought to be et al., 2004). Due to its binding to this enzyme the antibiotic
the ancestors of the naturally occurring chromosomally mediated prevents peptide chain elongation. The substrate spectrum of
-lactamase in many bacterial genera (Bradford, 2001). chloramphenicol includes Gram-positive and Gram-negative, aer-
Although plasmid-encoded penicillinase arose much earlier in obic and anaerobic bacteria. Chloramphenicol analogs including
Gram-positives in Staphylococcus aureus, due to the use of peni-
cillin (Aarestrup and Jensen, 1998), the rst plasmid-mediated 1 www.lahey.org/Studies
Amber class A Number of Amber class B Number of Amber class C Number of Amber class D Number of
-lactamases variants* -lactamases variants* -lactamases variants* -lactamases variants*
and ESBLs and MBLs and ESBLs and ESBLs
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van Hoek et al. Acquired antibiotic resistance genes
the uorinated derivative orfenicol have a similar spectrum of target, they inhibit the subsequent transglycosylation reaction by
activity. steric hindrance. (Gao, 2002; Klare et al., 2003).
Group Gene Gene(s) included Mechanism Length Accession Coding region Genera
(nt) number
Type A-1 catA1 cat, catI, pp-cat Inactivating 660 V00622 244..903 Acinetobacter, Escherichia,
enzyme Klebsiella, Salmonella, Serratia,
Shigella
Type A-2 catA2 cat, catII Inactivating 642 X53796 187..828 Aeromonas, Agrobacterium,
enzyme Escherichia, Haemophilus,
Photobacterium, Salmonella
Type A-3 catA3 cat, catIII Inactivating 642 X07848 272..913 Actinobacillus, Edwardsiella,
enzyme Klebsiella, Mannheimia,
Pasteurella, Shigella
Type A-4 Cat Inactivating 654 M11587 880..1533 Proteus
enzyme
Type A-5 Cat Inactivating 663 P20074* 1002758..1003420 Streptomyces
enzyme
Type A-6 cat86 Inactivating 663 K00544 145..807 Bacillus
enzyme
Type A-7 cat(pC221) cat, catC Inactivating 648 X02529 2267..2914 Bacillus, Enterococcus,
enzyme Lactobacillus, Staphylococcus,
Streptococcus
Type A-8 cat(pC223) cat Inactivating 648 AY355285 1000..1647 Enterococcus, Lactococcus,
enzyme Listeria, Staphylococcus,
Streptococcus
Type A-9 cat(pC194) cat, cat-TC Inactivating 651 NC_002013 1260..1910 Bacillus, Enterococcus,
enzyme Lactobacillus, Staphylococcus,
Streptococcus
Type A-10 Cat Inactivating 687 AY238971 1055..1741 Bacillus
enzyme
Type A-11 catP catD Inactivating 624 U15027 2953..3576 Clostridium, Neisseria
enzyme
Type A-12 catS Inactivating 492 X74948 1..492 Streptococcus
enzyme
Type A-13 Cat Inactivating 624 M35190 309..932 Aeromonas, Campylobacter
enzyme
Type A-14 Cat Inactivating 651 S48276 479..1129 Listonella, Photobacterium,
enzyme Proteus
Type A-15 catB Inactivating 660 M93113 145..804 Clostridium
enzyme
Type A-16 catQ Inactivating 660 M55620 459..1118 Clostridium, Streptococcus
enzyme
Type B-1 catB1 cat Inactivating 630 M58472 148..777 Agrobacterium
enzyme
Type B-2 catB2 Inactivating 633 AF047479 5957..6589 Acinetobacter, Aeromonas,
enzyme Bordetella, Escherichia,
Klebsiella, Pasteurella,
Pseudomonas, Salmonella
Type B-3 catB3 catB4, catB5, Inactivating 633 AJ009818 883..1515 Acinetobacter, Aeromonas,
catB6, catB8 enzyme Bordetella, Enterobacter,
Escherichia, Klebsiella,
Kluyvera, Morganella,
Pseudomonas, Salmonella,
Serratia, Shigella
(Continued)
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van Hoek et al. Acquired antibiotic resistance genes
Table 3 | Continued
Group Gene Gene(s) included Mechanism Length Accession Coding region Genera
(nt) number
Adapted from Partridge et al. (2009), Schwarz et al. (2004). Partial sequence. *Protein accession number, nucleotide sequence not available in DNA library.
(Continued)
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van Hoek et al. Acquired antibiotic resistance genes
Table 4 | Continued
(Continued)
Table 4 | Continued
(Continued)
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van Hoek et al. Acquired antibiotic resistance genes
Table 4 | Continued
Quinolones inhibit the action of DNA gyrase and topoiso- inhibition, was reported nearly a decade later (Martnez-Martnez
merase IV, two enzymes essential for bacterial DNA replication et al., 1998).
and as a result the microbes are killed. (Hooper, 1995, 2000). DNA Currently ve families of qnr genes have been reported; qnrA
gyrase is a tetrameric enzyme composed of 2 GyrA and 2 GyrB sub- (7), qnrB (39), qnrC (1), qnrD (1), and qnrS (4). The number
units. The topoisomerase IV has a similar structure, comprised of in between brackets indicates the variants known of each type
2 A and 2 B subunits, encoded by parC and parE, respectively. The (Jacoby et al., 2008; Cattoir and Nordmann, 2009; Cavaco et al.,
four genes coding for the subunits of these enzymes are the targets 2009; Strahilevitz et al., 2009; Torpdahl et al., 2009). Because of
for resistance mutations (see below). the increasing number of qnr genes a database has been con-
structed and will be maintained to assign further allele numbers
Resistance mechanism to novel variants2 . Very recently an additional family has been
For decades, the mechanisms of resistance to quinolones were described, qnrAS in the sh pathogen Aliivibrio salmonicida (Sun
believed to be only chromosome-encoded, however, recently three et al., 2010). Table 5 describes all known qnr families and their
plasmid-mediated resistance mechanisms have been reported variants, together with the gene lengths, accession numbers, and
(Robicsek et al., 2006a; Courvalin, 2008; Martnez-Martnez et al., in which bacterial genera they have been identied so far.
2008). The chromosome-encoded resistance result in either a The second type of plasmid located quinolone resistant gene is
decreased outer-membrane permeability related to porin loss, to a cr variant of aac(6 )-Ib, aac(6 )-Ib-cr, responsible for low-level
the (over)expression of naturally occurring efux pumps or muta- ciprooxacin resistance. It encodes an aminoglycoside acetyltrans-
tions of the molecular targets DNA gyrase and topoisomerase IV ferase, called AAC(6 )-Ib-cr which has two amino acid changes,
(Hooper, 2000; Ruiz, 2003; Jacoby, 2005). In the latter case muta- Trp102Arg and Asp179Tyr. These substitutions are responsible for
tions occur at specic quinolone resistance determining regions the enzymes ability to acetylate ciprooxacin (Park et al., 2006;
(QRDR) in the genes gyrA, gyrB, parC, and parE encoding the Robicsek et al., 2006b; Strahilevitz et al., 2009).
subunits of DNA gyrase and topoisomerase IV. Not surprisingly The third mechanism is qepA, a plasmid-mediated efux
this QRDR is situated on the DNA-binding surface of the enzymes pump which can extrude hydrophilic uoroquinolones, e.g.,
(Jacoby, 2005). ciprooxacin and enrooxacin (Prichon et al., 2007;Yamane et al.,
Although the possibility of the existence of plasmid-mediated 2007). A variant of this resistance pump, QepA2, was identied in
resistance was already suggested in 1990 (Courvalin, 1990), the an E. coli isolate from France (Cattoir et al., 2008).
rst actually identied plasmid-mediated quinolone resistance
gene, a qnr determinant, which encodes for a protein that pro-
tects DNA gyrase and type IV topoisomerase from quinolone 2 www.lahey.org/qnrstudies
Frontiers in Microbiology | Antimicrobials, Resistance and Chemotherapy September 2011 | Volume 2 | Article 203 | 16
van Hoek et al. Acquired antibiotic resistance genes
tet (O/W/O; Levy et al., 2005; Stanton et al., 2005; van Hoek et al., group are at least 474 nucleotides (nt) long (157 amino acids,
2008). aa), whereas the dfrB genes are 237 nt in length (78 aa). Cur-
There are currently over 40 different acquired tetracycline resis- rently six plasmid-mediated families can be distinguished with
tance determinants recognized, i.e., 38 tet (tetracycline resistance) relatively few dfr determinants originating from Gram-positive
and 3 otr (oxytetracycline resistance) genes, additionally 1 tcr gene bacteria. (Table 7). The dfrK gene is the newest addition to the
has been identied (Roberts, 1996, 2005; Brown et al., 2008; see trimethoprim resistance determinant family (Kadlec and Schwarz,
Table 6). Among these 25 of the tet, 2 of the otr genes and the 2009). In contrast to the latest reported DHFRs, the oldest fami-
only tcr determinant code for efux pumps, whereas 10 tet and lies, dfrA and dfrB, each contain several members (Roberts, 2002;
1 otr code for a RPP. The enzymatic inactivation mechanism can Levings et al., 2006). For example, the dfrA group accommodates
be attributed to 3 tet genes. The tet (U) determinant represents over 30 genes. Determinant dfrA27 is the newest reported DHFR
an unknown tetracycline resistance mechanism since its sequence gene among Gram-negatives (Wei et al., 2009), although a newer,
does not appear to be related to either efux or RPPs, nor to however unpublished, dfrA variant is present in the public DNA
the inactivation enzymes (Table 6). The efux and RPP encoding library and some genes apparently have changed nomenclature
genes are found in members of Gram-positive, Gram-negative, (Table 7). Among this family two sub-families can be distinguished
aerobic, as well as anaerobic bacterial species. In contrast the enzy- (Adrian et al., 2000). The dfrA1-group with 12 different genes
matic tetracycline inactivation mechanism has so far only been share 6490% identity on amino acids level. The dfrA12-group,
identied in Gram-negatives (Table 6). The tet (M) has the broad- with ve members, display 84% amino acid identity and similar
est host range of all tetracycline resistance genes, whereas tet (B) trimethoprim-inhibition proles. The additional dfrA genes are
gene has the widest range among the Gram-negative microbes. less related to each other, some have even less than 25% amino acid
In recent years published data indicate that there are increasing sequence identity. In contrast to the dfrA family, the dfrB group is
numbers of Gram-negative bacteria that carry Gram-positive tet somewhat smaller, with only eight reported genes (Levings et al.,
genes (Roberts, 2002). 2006; Partridge et al., 2009).
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van Hoek et al. Acquired antibiotic resistance genes
(Continued)
Table 6 | Continued
tet (O) Ribosomal 1,920 M18896 207..2126 Actinobacillus, Aerococcus, Anaerovibrio, Bidobacterium, Butyrivib-
protection rio, Campylobacter, Clostridium, Enterococcus, Eubacterium, Fusobac-
terium, Gemella, Lactobacillus, Megasphaera, Mobiluncus, Neisseria,
Peptostreptococcus, Psychrobacter, Staphylococcus, Streptococcus
tet (Q) Ribosomal 1,926 Z21523 362..2287 Anaerovibrio, Bacteroides, Capnocytophaga, Clostridium, Eubacterium,
protection Fusobacterium, Gardnerella, Lactobacillus, Mitsuokella, Mobiluncus, Neis-
seria, Peptostreptococcus, Porphyromonas, Prevotella, Ruminococcus,
Selenomonas, Streptococcus, Subdoligranulum, Veillonella
tet (S) Ribosomal 1,926 L09756 447..2372 Enterococcus, Lactobacillus, Lactococcus, Listeria, Staphylococcus,
protection Streptococcus, Veillonella
tet (T) Ribosomal 1,956 L42544 478..2433 Lactobacillus, Streptococcus
protection
tet (U) Unknown 318 U01917 413..730 Enterococcus, Staphylococcus, Streptococcus
tet (V) Efux 1,260 AF030344 462..1721 Mycobacterium
tet (W) Ribosomal 1,920 AJ222769 3687..5606 Acidaminococcus, Actinomyces, Arcanobacterium, Bacillus, Bacteroides,
protection Bidobacterium, Butyrivibrio, Clostridium, Fusobacterium, Lactobacil-
lus, Megasphaera, Mitsuokella, Neisseria, Porphyromonas, Prevotella,
Roseburia, Selenomonas, Staphylococcus, Streptococcus, Streptomyces,
Subdoligranulum, Veillonella
tet (X) Enzymatic 1,167 M37699 586..1752 Bacteroides, Sphingobacterium
tet (Y) Efux 1,176 AF070999 1680..2855 Aeromonas, Escherichia, Photobacterium
tet (Z) Efux 1,155 AF121000 11880..13034 Corynebacterium, Lactobacillus
tet (30) Efux 1,185 AF090987 1130..2314 Agrobacterium
tet (31) Efux 1,233 AJ250203 1651..2883 Aeromonas
tet (32) Ribosomal 1,920 DQ647324 181..2100 Enterococcus, Eubacterium, Clostridium, Streptococcus
protection
tet (33) Efux 1,224 AJ420072 22940..24163 Corynebacterium
tet (34) Enzymatic 465 AB061440 306..770 Aeromonas, Pseudomonas, Serratia, Vibrio
tet (35) Efux 1,110 AF353562 2213..3322 Stenotrophomonas, Vibrio
tet (36) Ribosomal 1,923 AJ514254 2534..4456 Bacteroides, Clostridium, Lactobacillus
protection
tet (37) Enzymatic 327 AF540889 1..327 Uncultured
tet (38) Efux 1,353 AY825285 1..1353 Staphylococcus
tet (39) Efux 1,188 AY743590 749..1936 Acinetobacter
tet (40) Efux 1,221 AM419751 14211..15431 Clostridium
tet (41) Efux 1,182 AY264780 1825..3006 Serratia
tet (42) Efux 1,287 EU523697 687..1973 Bacillus, Microbacterium, Micrococcus, Paenibacillus, Pseudomonas,
Staphylococcus
tet (43) Efux 1,560 GQ244501 60..1619 Uncultured
tet (44) Ribosomal 1,923 FN594949 25245..27167 Campylobacter
protection
et al., 2009; Aune and Aachmann, 2010; Burton and Dubnau, an origin of transfer and genes encoding functions that allow them
2010). to transfer to new hosts via conjugation (Smillie et al., 2010). Plas-
mids that harbor conjugation genes are called conjugative and
CONJUGATIVE ELEMENTS (PLASMIDS) plasmids that only contain an origin of transfer (oriT ) but no
Typically plasmids are extra chromosomal elements that contain conjugation genes are called mobilizable as they can make use of
their own origin of replication. They have been found in almost the conjugation functions of conjugative plasmids to transfer to a
all bacterial genera and the simplest of these elements just contain new host.
an origin of replication and genes encoding replication functions, In addition to functions involved in replication and transfer
e.g., see Chambers et al. (1988). Plasmids also commonly contain plasmids commonly encode resistance to antibiotics. If a resistance
Frontiers in Microbiology | Antimicrobials, Resistance and Chemotherapy September 2011 | Volume 2 | Article 203 | 20
van Hoek et al. Acquired antibiotic resistance genes
dfrA1 dfrA1-group dhfrIb, dfr1, dhfrI 474 X00926 236..709 Actinobacter, Enterobacter, Escherichia, Klebsiella,
Morganella, Proteus, Pseudomonas, Salmonella,
Serratia, Shigella, Vibrio
dfrA3 489 J03306 103..591 Salmonella
dfrA5 dfrA1-group dhfrV, dfrV 474 X12868 1306..1779 Aeromonas, Enterobacter, Escherichia, Klebsiella,
Salmonella, Vibrio
dfrA6 dfrA1-group dfrVI 474 Z86002 336..809 Escherichia, Proteus, Vibrio
dfrA7 dfrA1-group dhfrVII, dfrVII, dfrA17 474 X58425 594..1067 Actinobacter, Escherichia, Proteus, Salmonella,
Shigella
dfrA8 510 U10186 711..1220 Shigella
dfrA9 534 X57730 726..1259 Escherichia
dfrA10 564 L06418 5494..6057 Actinobacter, Escherichia, Klebsiella, Salmonella
dfrA12 dfrA12-group dhfrXII, dfr12 498 Z21672 310..807 Actinobacter, Aeromonas, Enterobacter, Enterococ-
cus, Citrobacter, Klebsiella, Pseudomonas, Serratia,
Salmonella, Staphylococcus
dfrA13 dfrA12-group 498 Z50802 718..1215 Escherichia
dfrA14 dfrA1-group dhfrIb 474 Z50805 72..545 Achromobacter, Aeromonas, Escherichia, Klebsiella,
Salmonella, Vibrio
dfrA15 dfrA1-group dhfrXVb 474 Z83311 357..830 Enterobacter, Klebsiella, Morganella, Proteus,
Pseudomonas, Salmonella, Vibrio
dfrA16 dfrA1-group dhfrXVI, dfr16 474 AF077008 115..588 Aeromonas, Escherichia, Salmonella
dfrA17 dfrA1-group dhfrXVII, dfr17 474 AB126604 98..571 Actinobacter, Enterobacter, Klebsiella, Pseudomonas,
Salmonella, Serratia, Shigella, Staphylococcus
dfrA18 dfrA19 570 AJ310778 7004..7573 Enterobacter, Klebsiella, Salmonella
dfrA20 510 AJ605332 1304..1813 Pasteurella
dfrA21 dfrA12-group dfrxiii 498 AY552589 1..498 Klebsiella, Salmonella
dfrA22 dfrA12-group dfr22, dfr23 498 AJ628423 325..822 Escherichia, Klebsiella
dfrA23 561 AJ746361 6743..7303 Salmonella
dfrA24 558 AJ972619 83..640 Escherichia
dfrA25 dfrA1-group 459 DQ267940 54..512 Citrobacter, Salmonella
dfrA26 552 AM403715 303..854 Escherichia
dfrA27 dfrA1-group dfr 474 EU675686 2543..3016 Escherichia
dfrA28 dfrA1-group 474 FM877476 116..589 Aeromonas
dfrA29 dfrVII, dfrA7 472 AM237806 615..1086 Salmonella
dfrA30 dhfrV 474 AM997279 705..1178 unknown
dfrA31 dfr6 474 AB200915 1832..2305 Vibrio
dfrA32 dfrA1-group 474 GU067642 535..1008 Laribacter, Salmonella
dfrA33 dfrA12-group 498 FM957884 88..585 Unknown
dfrB1 dhfrIIa, dfr2a 237 U36276 717..953 Aeromonas, Bordetella, Escherichia, Klebsiella
dfrB2 dhfrIIb, dfr2b 237 J01773 809..1045 Escherichia
dfrB3 dhfrIIc, dfr2c 237 X72585 5957..6193 Aeromonas, Enterobacter, Escherichia, Klebsiella
dfrB4 dfr2d 237 AJ429132 69..305 Aeromonas, Escherichia, Klebsiella
dfrB5 dfr2e 237 AY943084 2856..3092 Pseudomonas
dfrB6 237 DQ274503 394..630 Salmonella
dfrB7 237 DQ993182 244..480 Aeromonas
dfrB8 249 GU295656 1048..1296 Aeromonas
dfrC dfrA 486 Z48233 337..822 Staphylococcus
dfrD 489 Z50141 94..582 Listeria, Staphylococcus
dfrG 498 AB205645 1013..1510 Enterococcus, Staphylococcus
dfrK 492 FM207105 2788..3279 Staphylococcus
gene is on a conjugative or mobilizable plasmid then it has the head, and specialized, in which the DNA adjacent to the phage
potential to transfer to new hosts. Some plasmids have a broad insertion site is packaged.
host range and can transfer between different species whereas oth-
ers have a much narrower host range and are conned to one genus TRANSLOCATION WITHIN GENOMES
or species. There are also plasmids that have the capability of trans- The simplest of the mobile genetic elements are insertion sequence
ferring to a particular host but cannot replicate in the new host or (IS). These elements just consist of the gene required for element
do not replicate well. In these circumstances the plasmid may be mobility and the inverted repeat at the ends of the element. IS
lost, however if it contains a resistance gene on a transposon this elements can be as short as 1Kb (Siguier et al., 2006). When
genetic element can translocate to the bacterial chromosome and these elements contain accessory genes not involved in element
be maintained in the absence of the plasmid. Therefore a plasmid translocation they are called transposons. A simple transposon
does not necessarily need to be maintained in a particular host in will contain an accessory gene (often encoding AR) together
order to contribute to the spread of resistance. with the transposase (for examples of each type of element see
Both circular and linear plasmids have been described. Circular Roberts et al., 2008). There are more complex classes of trans-
plasmids have in general been more intensively investigated then posons that move using different mechanisms including class II
linear plasmids. This probably reects the relative ease which they transposons.
can be separated from the bacterial chromosome. Nonetheless lin- The transposons mentioned above are not capable of conjugal
ear plasmids have now been relatively well characterized and have transfer to other bacteria and in order for them to be disseminated
been shown to convey advantageous phenotypes on the host. Like they need to be contained within a conjugative element. However
circular plasmids linear plasmids are often capable of conjugation some of ICE elements as well as being able to transfer to new
(Meinhart et al., 1997; Chaconas and Kobryn, 2010). hosts (see above) are also able to transpose to new genomic sites.
Some (resistance) plasmid types cannot coexist in a microbial Their ability to use different integration sites in the chromosomes
cell and this fact gave rise to the division into incompatibility depends on the type of recombinases they contain. For example
groups (Couturier et al., 1988). Four major groups have been Tn916 can use a large number of different integration sites in
dened on the basis of genetic relatedness and pilus structure: most hosts (reviewed in Roberts and Mullany, 2009). However
IncF group (containing IncC, IncD, IncF, IncJ, and IncS), IncI some elements are highly site-specic such as Tn916 (Wozniak
group (including IncB, IncI, and IncK), IncP group (consisting of and Waldor, 2010). Presumably elements like Tn916 have evolved
IncM, IncP, IncU, and IncW), and Ti. to use different integration sites in order to increase their host
range. Elements that can only use a particular number of inser-
CONJUGATIVE ELEMENTS (INTEGRATIVE) tion sites are limited in the hosts they can use if the site is mutated
The integrative conjugative elements (ICE), also called conjugative or occupied.
transposons (Roberts et al., 2008), like the conjugative plasmids
contain an origin of transfer and the genes required to make the GENE CAPTURE ELEMENTS
conjugation apparatus. Unlike plasmids these elements do not Integrons are genetic elements that include components of a site-
contain an origin of replication and have to integrate into a repli- specic recombination system enabling them to capture and mobi-
con in order to be maintained. This replicon can be either plasmid lize genes, in particular AR determinants (Stokes and Hall, 1989;
or chromosome. This gives them an advantage over plasmids as Rechia and Hall, 1995; Fluit and Schmitz, 1999; Depardieu et al.,
they do not have to have replication machinery that is compatible 2007). They harbor an intI gene, encoding a site-specic integrase
with the host so tend to have a larger host range than plasmids. of the tyrosine recombinase family that carries out recombination
Integrative conjugative elements are a highly heterogeneous between two distinct target sites, i.e., an attI recombination site
group of genetic elements with different properties and host and a 59-base element (attC site) where attI is the target site for
ranges. However in general they do have a modular organiza- cassette integration and a promoter (Hall and Stokes, 1993; Hall
tion, i.e., a conjugation, recombination, regulation, and accessory and Collis, 1995; Rechia and Hall, 1997; Mazel, 2006). In contrast
modules. The latter commonly contains genes encoding AR. to transposons integrons are not anked by repeat sequences, in
There are also integrative elements that do not contain the con- addition they do not include any genes encoding proteins that
jugation region but can by mobilized by co-resident conjugative catalyze their movement. HGT of integrons to other bacteria is
ICE or conjugative plasmids. Again these can mediate the spread mostly mediated by plasmids or transposons.
of AR. There have been a number of comprehensive reviews in The intI genes have been used as a basis for grouping integrons
this area (Roberts and Mullany, 2009; Frost and Koraimann, 2010; into classes. Currently, four classes are recognized; those carry-
Wozniak and Waldor, 2010). ing intI1 are dened as class 1, intI2 as class 2, intI3 as class 3, and
intI4 as class 4 (Carattoli, 2001; Partridge et al., 2009).
TRANSDUCTION
There have been examples of AR genes, and even entire mobile FACTORS INFLUENCING ACQUISITION OF MOBILE GENETIC ELEMENTS
genetic elements, being mobilized by transduction (Willi et al., The ability of mobile genetic elements containing AR genes to
1997; Del Grosso et al., 2011). Transduction is a process in which spread is modulated by a range of factors including, selective pres-
the phage particles are packaged with bacterial DNA instead of sures in the environment, host factors, and properties of the genetic
phage. There are two type of transduction, generalized in which elements themselves. Each of these factors will be examined in turn
any segment of bacterial DNA can be packaged into the phage in the next sections.
Frontiers in Microbiology | Antimicrobials, Resistance and Chemotherapy September 2011 | Volume 2 | Article 203 | 22
van Hoek et al. Acquired antibiotic resistance genes
Specic host encoded factors anti-restriction proteins which have been shown to mimic DNA
Bacteria have a number of systems that protect them from incom- and are recognized by the restriction enzyme. The anti-restriction
ing DNA, including restriction/modication systems and CRISPR- protein ArdA from Tn916 is one of the best characterized
Cas systems (Makarova et al., 2011). These systems although (McMahon et al., 2009).
mechanistically very different have the same end point of iden- Many transposons and ICE can transpose into essential genes.
tifying and destroying foreign DNA. Restriction systems work by If this happens the host will die, to get around this some mobile ele-
identifying particular sequences in the incoming DNA that have ments are site-specic or preferentially target inter-genic regions
not been protected by methylation and digesting them. CRISPRs (Cookson et al., 2011). Also most transposable elements (includ-
act as a memory of past infection by a mobile element and can ing ICE) are tightly regulated so that they only transpose at low
destroy that element if the bacterium encounters it again. Both frequency or transpose when the bacteria are stressed, such as
these systems can be effective in stopping the spread of phage, antibiotics in their environment (reviewed in Roberts and Mul-
ICE, and plasmids. lany, 2009; Wozniak and Waldor, 2010). For example members of
A specic host factor that attracts mobile elements has been the CTndot family of ICE transfer at a much higher frequency in
documented in the pheromone responsive systems, in which a the presence of tetracycline (the antibiotic to which they encode
plasmid less recipient secrets a pheromone to which plasmids con- resistance). This is an advantageous response for both the element
taining strains respond and transfer their plasmid to the recipients and the host bacteria (Moon et al., 2005).
(Palmer et al., 2010).
Environmental factors
None specic host factors All the factors outlined in the previous sections are important
Some none specic factors that can act as barriers to HGT have in modulating the spread of AR but obviously if antibiotics are
been eluded to above such as not having the target site for a par- present in the environment there is strong selective pressure for
ticular ICE or having incompatible replication systems that stop spread of resistance and those factors that promote the spread of
plasmids replicating in a particular host. Also the architecture of resistance will be selected for and those stopping the spread of
the cell surface my not allow the conjugation systems of all mobile mobile elements selected against.
elements to work productively. Additionally one member of a mat- Gene transfer is also more likely in environments where bac-
ing pair may produce inhibitory substances. Bacteria produce a teria are in close proximity to each other and in relatively high
number of antimicrobial products the most common being the density such as the gut and oral cavity. In order to control the
peptide antibiotics. The best understood are the colicins produced spread of resistance it is important to have an understanding of
by E. coli. Gram-positive bacteria also produce a diverse array of the molecular biology of the different mobile genetic elements and
antimicrobial peptides (Riley and Wertz, 2002). of the ecology of the environments in which spread is likely.
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