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Antimicrobial Agents and Chemotherapy, October 2000, p. 2876-2879, Vol. 44, No. 10
Research and Medical Service, John D. Dingell
VA Medical Center, and Wayne State University School of Medicine,
Detroit, Michigan 482011; Departments of
Biologic and Materials Sciences and Microbiology and Immunology,
University of Michigan, Ann Arbor, Michigan
481092; William Beaumont Hospital, Royal
Oak, Michigan 480733; and
Schering-Plough Research Institute, Kenilworth, New Jersey
070334
Received 22 December 1999/Returned for modification 6 March
2000/Accepted 17 July 2000
A new high-level gentamicin resistance gene, designated
aph(2")-Ib, was cloned from Enterococcus
faecium SF11770. The deduced amino acid sequence of the 897-bp
open reading frame of aph(2")-Ib shares homology with the
aminoglycoside-modifying enzymes AAC(6')-APH(2"), APH(2")-Ic, and
APH(2")-Id. The observed phosphotransferase activity is designated
APH(2")-Ib.
High-level gentamicin resistance
(MIC (This work was presented in part at the 37th Interscience Conference on
Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, 28 September to 1 October 1997.)
Enterococci were identified by conventional biochemical criteria
(9). E. faecium SF11770 is a blood culture
isolate from a patient in Detroit, Mich. Escherichia
coli DH5 Plasmid DNA minipreparations and total genomic DNA were obtained by a
modified alkaline lysis method (20). Methods for restriction endonuclease digestion, agarose gel electrophoresis of DNA,
transformation by using calcium chloride or electroporation, and
Southern blot hybridization were performed as previously described
(2, 7, 19). The phosphocellulose paper binding assay was
performed as previously described (4, 17). Oligonucleotide
primers were synthesized by GIBCO BRL Life Technologies (Gaithersburg, Md.). The probes for aac(6')-Ie-aph(2")-Ia,
aph(2")-Ic, and aph(2")-Id were prepared as
described previously (4, 10, 19). DNA to be sequenced was
obtained as described in the Qiagen (Chatsworth, Calif.) plasmid
handbook. The vectors pBluescript II KS(+) (Stratagene Cloning Systems,
La Jolla, Calif.) and pMW119 (Nippon Gene Corporation, Toyama, Japan)
were used in standard cloning experiments (2). Nucleotide
sequencing was performed at the DNA Sequencing Core, University of
Michigan, Ann Arbor. Computer analysis was performed with MacVector
software, version 6.0, and AssemblyLIGN, version 1.0.9 (Oxford
Molecular Group, Oxford, United Kingdom). The GenBank database was
searched with the BLAST program from the National Center for
Biotechnology Information (1). Amino acid sequences were
compared by using the Gap Analysis Program from the University of
Wisconsin Genetics Computer Group (6). The PCR primers used for detecting the aac(6')-Ie-aph(2")-Ia gene were
5'-GAGCAATAAGGGCATACCAAAAATC-3' and
5'-CCGTGCATTTGTCTTAAAAAACTGG-3'. The primers for detecting aph(2")-Ib were 5'-TATGGATCCATGGTTAACTTGGACGCTGAG-3'
and
5'-AT TAAGCTTCCTGCTAAAATATAAACATCTCTGCT-3'. The
primers for detecting aph(2")-Ic were as previously reported
(4). The primers for detecting aph(2")-Id were
5'-GGTGGTTTTTACAGGAATGCCATC-3' and
5'-CCCTCTTCATACCAATCCATATAACC-3'.
Aminoglycoside MICs for E. faecium SF11770 are shown in
Table 1. The ampicillin MIC was 128 µg/ml, the streptomycin MIC was >2,000 µg/ml, and the vancomycin
MIC was >256 µg/ml. The probes for the
aac(6')-Ie-aph(2")-Ia, aph(2")-Ic, and
aph(2")-Id genes did not hybridize to Southern blots of
total cellular DNA from E. faecium SF11770. Filter matings,
with SF11770 as the donor and E. faecium GE1 or E. faecalis FA2-2 as the recipient, did not result in the transfer of
gentamicin resistance (the frequency was <1 × 10
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Detection of the High-Level Aminoglycoside
Resistance Gene aph(2")-Ib in Enterococcus
faecium
and
ABSTRACT
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500 µg/ml) in enterococci is predominantly mediated by
aac(6')-Ie-aph(2")-Ia, which encodes the bifunctional
aminoglycoside-modifying enzyme AAC(6')-APH(2") (10). Found
less commonly is aph(2")-Id, another gene recently reported
to be associated with high-level gentamicin resistance in enterococci
(19). The presence of high-level gentamicin resistance in
enterococci eliminates the synergistic killing usually seen when
gentamicin is combined with a cell wall-active agent, such as
ampicillin or vancomycin. aph(2")-Ic is a mid-level
gentamicin resistance gene isolated infrequently from enterococci that
eliminates the synergism between ampicillin and gentamicin, even though
the gentamicin MIC for strains containing this gene is typically only ca. 256 µg/ml (4). We describe the cloning and sequencing
of another aminoglycoside resistance gene, aph(2")-Ib, that
is associated with high-level gentamicin resistance in
Enterococcus faecium.
and E. coli DH10b were used as recipients
for electroporation and as hosts for maintaining recombinant plasmids.
E. faecium GE1 (8) and Enterococcus
faecalis FA2-2 (5) were the recipient strains in mating
experiments. Gentamicin was obtained from Fluka (Buchs, Switzerland).
Arbekacin and netilmicin were provided by Meiji Seika Kaisha (Tokyo,
Japan). All other antimicrobial agents were purchased from Sigma
Chemical Company (St. Louis, Mo.). Antimicrobial susceptibilities were
determined by a standard broth microdilution method (15).
Tests of synergistic killing were performed using a previously
described method (12), with some modifications. Synergy was
defined as a 2-log10 decrease in CFU/ml between the combination and its most active constituent after 24 h, with the number of surviving organisms in the presence of the combination being
2 log10 CFU/ml below the number of organisms in the
starting inoculum. Also, at least one of the drugs must be present in a concentration that does not affect the growth curve of the test organism when used alone. One hundred twenty-one enterococcal clinical
isolates (78 E. faecalis, 41 E. faecium, 1 Enterococcus raffinosus, and 1 Enterococcus
gallinarum isolate) with high-level gentamicin resistance from
separate patients in six Detroit, Mich., area hospitals were used to
screen for the presence of the new gene. This collection included
isolates that were part of clonal outbreaks in the Detroit area and had
been previously screened for aph(2")-Id (19).
9
per recipient CFU). Electroporation of a plasmid preparation from
SF11770 into competent E. faecalis OG1RF cells also did not result in the selection of gentamicin-resistant transformants. In tests
of bactericidal synergistic killing against E. faecium SF11770, ampicillin at 64 µg/ml combined with arbekacin at 8 or 16 µg/ml produced a 3- to 4-log10 decrease in CFU per
milliliter at 24 h compared to the most active agent (ampicillin)
(Fig. 1A and B). However, since the
growth curve of the organism with either ampicillin or arbekacin alone
was slightly different than the growth with no antimicrobial agent,
this did not fulfill the strict criteria for synergistic killing.
Ampicillin at 64 µg/ml combined with arbekacin at 2 or 4 µg/ml did
not produce greater killing at 24 h than either drug alone (Fig.
1A and C). The combination of ampicillin (64 µg/ml) and gentamicin
(16 µg/ml) also did not produce greater killing at 24 h than
either drug alone (Fig. 1D).
TABLE 1.
Susceptibilities of E. faecium SF11770,
E. coli KHE5-2, and E. coli DH10b(pMW119)
to aminoglycosides
View larger version (24K):
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FIG. 1.
Tests of synergistic killing against E. faecium SF11770. 
, no antimicrobial; 
, ampicillin (64 µg/ml); 
, arbekacin (16 µg/ml); 
, ampicillin (64 µg/ml)
plus arbekacin (16 µg/ml); 
, arbekacin (8 µg/ml); 
,
ampicillin (64 µg/ml) plus arbekacin (8 µg/ml); 
, arbekacin (4 µg/ml); 
, ampicillin (64 µg/ml) plus arbekacin (4 µg/ml); 
,
arbekacin (2 µg/ml); 
, ampicillin (64 µg/ml) plus arbekacin (2 µg/ml); 
, gentamicin (16 µg/ml); and 
, ampicillin (64 µg/ml) plus gentamicin (16 µg/ml).
Partial Sau3AI digestions of total genomic DNA from SF11770
were ligated to pBluescript II KS(+) digested with BamHI and
dephosphorylated with calf intestine alkaline phosphatase. After
electroporation of the ligated products, selection on Luria-Bertani
plates containing 25 µg of gentamicin per ml yielded small numbers of
gentamicin-resistant E. coli DH5 transformants.
Additional subcloning experiments using HindIII and
EcoRI and the low-copy-number vector pMW119 yielded a
gentamicin-resistant E. coli DH10b transformant, designated KHE5-2, which contained a 1.5-kb cloned fragment. Aminoglycoside MICs
for E. coli KHE5-2 and E. coli DH10b(pMW119) are
shown in Table 1.
Nucleotide sequencing of the 1.5-kb fragment revealed the presence of an 897-bp open reading frame, with a G+C content of 32%, whose predicted amino acid sequence showed homology with sequences of aminoglycoside phosphotransferases deposited in GenBank. The highest homology was seen with the deduced proteins from the aph(2")-Id (32% identity and 49% similarity) and aac(6')-Ie-aph(2")-Ia genes (33% identity and 51% similarity with the APH(2")-Ia domain). Less closely related was the aph(2")-Ic gene (25% identity and 44% similarity). The gentamicin resistance gene has been designated aph(2")-Ib. The aminoglycoside phosphotransferase activity, designated APH(2")-Ib, was confirmed by the phosphocellulose paper binding assay. Crude extracts from E. coli KHE5-2 exhibited phosphotransferase activity with all of the aminoglycoside substrates listed in Table 1, except for neomycin. aph(2")-Ib was cloned by PCR into the shuttle vector pWM401 (20), the recombinant DNA was electroporated into competent E. faecalis JH2-2 cells (gentamicin MIC = 16 µg/ml), and high-level gentamicin-resistant (MIC > 2,000 µg/ml) E. faecalis transformants were obtained.
Evaluation of the presence of gentamicin resistance genes by PCR showed
that 6 of 121 isolates (5%) were negative for the aac(6')-Ie-aph(2")-Ia, aph(2")-Ic, and
aph(2")-Id genes. All six were positive for the
aph(2")-Ib gene by PCR. These six isolates (five from blood
and one from stool cultures) were all vancomycin-resistant E. faecium from three hospitals in Detroit, Mich., and five belonged to the same clonal group, as determined by pulsed-field gel
electrophoresis. The gentamicin MICs for all six were 1,024 µg/ml,
and the arbekacin MICs ranged from 8 to 32 µg/ml. All of the 121 isolates possessed one of the four gentamicin resistance genes tested,
and none possessed more than one of the genes tested.
aph(2")-Ib is now the fourth aminoglycoside resistance gene detected in Enterococcus spp. that eliminates the bactericidal synergistic effect of ampicillin and gentamicin against enterococci. The origin of the aph(2")-I family of genes remains uncertain. aac(6')-Ie-aph(2")-Ia is also found in staphylococci and streptococci (18; M. Galimand, G. Gerbaud, P. Courvalin, and T. Lambert, Abstr. 39th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 833, 1999), and it has been proposed that aac(6')-Ie-aph(2")-Ia was transmitted initially from staphylococci to enterococci (14). However, aph(2")-Ib, aph(2")-Ic, and aph(2")-Id have not yet been detected in staphylococci and thus are less likely to have been transmitted from staphylococci (21). When we compared the nucleic acid sequence of aph(2")-Ib to that of an unpublished aph(2") resistance gene from an E. coli clinical isolate from the former republic of Czechoslovakia (J. Petrin, R. Kuvelkar, M. Kettner, R. S. Hare, G. H. Miller, and K. J. Shaw, Cold Spring Harbor Bacteria Phage Meet., abstr. 197, 1995), we found that the two sequences were identical, except for four nucleotides (resulting in three amino acid changes). The 32% G+C content of aph(2")-Ib raises the possibility that this gene may have first originated in enterococci and then been transmitted to E. coli, since the G+C contents of Enterococcus spp. and E. coli are approximately 35 and 50%, respectively.
The aminoglycoside MIC profile of E. faecium SF11770 indicates various degrees of resistance to most of the clinically available aminoglycosides, except for arbekacin (Table 1). Arbekacin is a new aminoglycoside available in Japan, where it is used to treat gentamicin- and methicillin-resistant staphylococci (11, 13, 16). Although the combination of ampicillin and arbekacin at achievable concentrations in serum did not strictly fulfill the criteria for synergism against E. faecium SF11770, the combination with higher arbekacin concentrations did exhibit significantly greater killing of the organism than either agent alone. These preliminary findings need to be confirmed by in vivo data before arbekacin can be recommended for use in combination therapy against enterococci that possess aph(2")-Ib.
Nucleotide sequence accession number. The nucleotide sequence for aph(2")-Ib has been deposited in GenBank under accession number AF207840.
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ACKNOWLEDGMENTS |
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This study was supported in part by the Department of Veterans' Affairs.
We thank Haruyoshi Tomita, Stephen A. Lerner, and Sergei Vakulenko for helpful discussions, Liberty Chow for technical assistance, and Glenn W. Kaatz for help with Fig. 1.
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FOOTNOTES |
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* Corresponding author. Mailing address: Medical Service, John D. Dingell VA Medical Center, Detroit, MI 48201-1932. Phone: (313) 576-3310. Fax: (313) 576-1122. E-mail: aa2563{at}wayne.edu.
Present address: RW Johnson Pharmaceutical Research Institute, San
Diego, CA 92121.
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