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Antimicrob Agents Chemother. May 2005; 49(5): 1714–1719.
PMCID: PMC1087617

Relationship between Mutations in the gyrA Gene and Quinolone Resistance in Clinical Isolates of Corynebacterium striatum and Corynebacterium amycolatum

Abstract

Quinolone susceptibility was analyzed in 17 clinical isolates of Corynebacterium striatum and 9 strains of Corynebacterium amycolatum by the E-test method in Mueller-Hinton agar plates. The C. striatum ATCC 6940 strain was used as a control strain. The amplified quinolone resistance determining regions of the gyrA genes of C. amycolatum and C. striatum were characterized. Four in vitro quinolone-resistant mutants of C. amycolatum were selected and analyzed. Both in vivo and in vitro quinolone-resistant strains of C. amycolatum showed high levels of fluoroquinolone resistance in strains with a double mutation leading to an amino acid change in positions 87 and 91 or positions 87 and 88 (unusual mutation) of GyrA, whereas the same concomitant mutations at amino acid positions 87 and 91 in GyrA of C. striatum produced high levels of resistance to ciprofloxacin and levofloxacin but only showed a moderate increase in the MIC of moxifloxacin, suggesting that other mechanism(s) of quinolone resistance could be involved in moxifloxacin resistance in C. amycolatum. Moreover, a PCR-RFLP-NcoI of the gyrA gene was developed to distinguish between C. amycolatum and C. striatum species.

Corynebacteria, other than Corynebacterium diphtheriae, are ubiquitous and are part of the normal flora of the skin and mucous membrane. The isolation of this type of microorganisms is not usually of clinical relevance and is attributable to the contamination of the sample. However, these microorganisms have increasingly been recognized as pathogens (5, 9). Several case reports have described C. striatum as a cause of infections such as pneumonia (30), vertebral osteomyelitis (6), septicemia (17), and endocarditis (4). Similarly, several authors have described C. amycolatum as a pathogen (3, 14). The rise in the clinical importance of these new pathogens makes it necessary to know their susceptibility to the antimicrobial agents currently available. Although the data are limited (9), C. amycolatum has shown a multidrug resistance phenotype, presenting high rates of resistance to antibiotics such as ampicillin, aminoglycosides, ofloxacin, and doxycycline and only showing susceptibility to glycopeptides (16), whereas the rates of resistance for C. striatum are lower, showing only high percentages of resistance to clindamycin and ampicillin (16). These figures on antimicrobial resistance are in accordance with those published by Funke et al. (8), who reported high rates of resistance to many classes of antimicrobial agents. Furthermore, high levels of resistance to ciprofloxacin have been described (17-21). A multidrug-resistant strain of C. striatum only susceptible to rifampin and vancomycin has recently been reported (30). In spite of these high levels of resistance to quinolones in species of the genus Corynebacterium, no reports have been published on the mechanisms of resistance. Moreover, the activity of the new fluoroquinolones in comparison with ciprofloxacin has been described (7, 25, 26). Rolston et al. (25, 26) compared the activity of several new fluoroquinolones such as levofloxacin, moxifloxacin, or trovafloxacin to the activity of ciprofloxacin in a small collection of Corynebacterium sp. strains (without species identification), with moxifloxacin being the quinolone with the best activity (i.e., an MIC at which 90% of the isolates tested are inhibited of 2 μg/ml). Moreover, on comparing the activity of gemifloxacin and levofloxacin with older quinolones among known species of Corynebacterium, Martinez-Martinez et al. (18, 20) showed that C. amycolatum had higher rates of resistance than C. striatum. Therefore, the main aim of the present study was to investigate the mechanisms of resistance to these antimicrobial agents in these microorganisms.

MATERIALS AND METHODS

Bacterial strains.

C. amycolatum strains were isolated in the Hospital Universitario Virgen Macarena, Seville, Spain. C. striatum strains were isolated in the Departments of Microbiology of Hospital Clínic, Barcelona, Spain, Hospital Universitario Virgen Macarena, Seville, Spain, and Hospital Monte Naranco, Oviedo, Spain. All of the strains were identified by the API Coryne system (bioMérieux, Marcy l'Étoile, France), and two additional tests were performed to differentiate C. amycolatum and C. striatum, as described elsewhere (21). The C. striatum ATCC 6940 strain was used as a control strain.

Susceptibility testing.

The MICs of ciprofloxacin, levofloxacin, and moxifloxacin were determined by the E-test method (AB Biodisk, Solna, Sweden) in Mueller-Hinton agar plates at 37°C in an aerobic atmosphere. There are no specific guidelines by the National Committee for Clinical Laboratory Standards for the susceptibility testing of corynebacteria.

Amplification and sequence of QRDR of the gyrA gene.

To amplify the quinolone resistance determining region (QRDR) of the gyrA gene of C. amycolatum and C. striatum, a couple of degenerate primers for gyrA were first used. Based on this sequence a novel pair of specific primers for corynebacteria was designed: CorynA1 (GCG GCT ACG TAA AGT CC) and CorynA2 (CCG CCG GAG CCG TTC AT). The PCRs were performed as follows. One colony was resuspended in 25 μl of water and boiled for 10 min. Afterward, 25 μl of the 2× PCR mixture was added. The final concentrations were 0.5 μM for each primer, 200 mM deoxynucleoside triphosphate, 1.5 mM MgCl2, and 2.5 U of Taq polymerase. The PCR program was 96°C for 1 min, 55°C for 1 min, and 72°C for 1 min for 30 cycles, with a final extension of 72°C for 5 min. The PCR products were visualized in an agarose gel containing 0.5 μg of ethidium bromide/ml. The PCR products were then cleaned up with a commercial kit (Wizard SV Gel and PCR Clean-Up System; Promega, Madison, Wis.), and 4 μl was used to sequence the recovered PCR product with a BigDye sequence kit (v3.1; Applied Biosystems, Foster City, Calif.).

Selection of in vitro fluoroquinolone-resistant mutants of C. amycolatum.

An inoculum of ca. 109 CFU of the quinolone-susceptible C. amycolatum strain 1008 was spread on blood agar plates containing 1 mg of ciprofloxacin/ml (15 times the MIC), followed by incubation overnight to obtain first-step mutants. Second-step mutants were obtained by culturing the previously obtained mutant strain on blood agar plates containing 32 μg of ciprofloxacin/ml. The sequence of the gyrA gene, as well as the MICs of the fluoroquinolones of the first- and second-step mutants, was determined as described above.

PCR-RFLP of the QRDR of the gyrA gene.

The PCR product of the gyrA gene described above was subjected to digestion with the NcoI restriction enzyme. A total of 25 μl of the recovered PCR product was taken, and 2.5- and 1-μl portions of the restriction buffer and NcoI restriction enzyme were added, followed by incubation for 3 h at 37°C. The restriction patterns were then visualized in a 2% agarose gel containing 0.5 μg of ethidium bromide/ml.

RESULTS

Sequences of the QRDR of the gyrA gene.

The amplified fragment of the gyrA gene sequences obtained from the quinolone-susceptible C. amycolatum clinical strain and the C. striatum ATCC 6940 strain were added to GenBank under accession numbers AY559039 and AY559038. These sequences were used as wild-type sequences to find mutations in resistant strains.

The amino acid sequence of the fragment corresponding to the QRDR was compared to those of the GyrA from other gram-positive bacteria, such as Corynebacterium glutamicum, Staphylococcus aureus, Streptococcus pneumoniae, and Listeria monocytogenes, and to other microorganisms that do not have the parC gene, such as Helicobacter pylori, Campylobacter jejuni, and Mycobacterium tuberculosis (Fig. (Fig.1).1). Similarities in nucleotides and amino acid sequences in these sequences are presented in Table Table11.

FIG. 1.
Comparison of the amino acid sequence of the QRDR of the gyrA gene. The protein sequences were obtained based on the indicated GenBank accession numbers: C. amycolatum ( ...
TABLE 1.
Comparison of nucleotide and amino acid sequences of the QRDRs of the gyrA genes of C. striatum and C. amycolatum with other microorganisms

The nucleotide sequence of the gyrA gene of C. striatum and C. amycolatum showed a homology of 80.7%. Comparison of these sequences with those of other microorganisms demonstrated a high homology with the gyrA genes of C. glutamicum (85.7 and 81.3%, respectively) and M. tuberculosis (72.1 and 72.7%, respectively). It is interesting that there was a high degree of homology with M. tuberculosis, which also lacks the parC gene. The remaining compared sequences presented homologies of between 64 and 53%. Furthermore, when the amino acid sequences of these microorganisms were compared, similar results were found.

MICs of fluoroquinolones and mutations in the gyrA gene.

Two of nine strains of C. amycolatum isolates presented the lowest MICs of quinolones. The MICs of ciprofloxacin for these two strains were of 0.064 and 0.047 μg/ml; the MIC of levofloxacin was 0.094 μg/ml, and finally the MIC of moxifloxacin was 0.016 μg/ml. One strain showed a mutation in the amino acid codon Ser-87, generating a change to Arg and drastically increasing the MIC of ciprofloxacin to >32 μg/ml. The MICs of levofloxacin and moxifloxacin were also increased to 8 and 2 μg/ml, respectively. (The number of the amino acid position was taken from the amino acid sequence of GyrA from C. glutamicum.)

Two double mutations in the gyrA gene were observed in six C. amycolatum clinical isolates. The first double mutant observed in one strain showed a mutation at amino acid codon Ser-87 to Arg plus a novel mutation in an unusual position: amino acid codon Ile-89 to Val. In this strain the MIC of ciprofloxacin was of 32 μg/ml, and the MICs of levofloxacin and moxifloxacin increased to 24 and 6 μg/ml, respectively.

For the remaining five strains, the MICs of the three fluoroquinolones were determined to be >32 μg/ml. These strains carried a double mutation in the amino acid codon Ser-87 and Ala-88 of the gyrA gene, producing a change from Ser-87 to Arg and another unusual change from Ala-88 to Pro (Table (Table22).

TABLE 2.
Relationship between mutations in the QRDRs of the gyrA genes and the MICs for C. amycolatum

Fluoroquinolone-resistant mutants of C. amycolatum were obtained in vitro to ensure that the mutations observed in the clinical strains are sufficient to produce these high levels of MIC of fluoroquinolones. Three first-step, in vitro-selected ciprofloxacin resistant mutants, named CA1, CA2, and CA3, which were grown in 1 μg of ciprofloxacin/ml, were chosen for further analysis. All had one mutation in the amino acid codon Ser-87 changing to Arg, as observed in the clinical strains, and the MICs of the three fluoroquinolones—ciprofloxacin (>32 μg/ml), levofloxacin (8 μg/ml), and moxifloxacin (2 μg/ml)—were also the same. Second-step mutants were selected after culture of the first-step mutant (CA1) in 32 μg of ciprofloxacin/ml. In this case, the MICs of the fluoroquinolones tested for the three selected mutants (CA32A, CA32B, and CA32C) chosen for further analysis were >32 μg/ml, but the mutations were different. Mutants CA32A and CA32C presented the same double mutations as the clinical isolates (Ser87 to Arg and Ala-88 to Pro), whereas the other mutant (CA32B) showed a mutation in the amino acid codon Ser-87 and the second mutation in the amino acid codon Asp-91, changing to Tyr (Table (Table22).

Two of seventeen strains of C. striatum and the control strain ATCC 6940 were associated with the lowest quinolone MICs. The MIC of ciprofloxacin was between 0.094 to 0.125 μg/ml, and the MICs of levofloxacin and moxifloxacin were of 0.125 and 0.047 μg/ml, respectively. These three strains did not show any mutation in the QRDR of the gyrA gene. Four strains had a mutation at amino acid codon Ser-87 that changed the amino acid to Phe. The ciprofloxacin and levofloxacin MICs for these strains showed moderate increases from 1 to 3 and from 1 to 2 μg/ml, respectively. However, the MICs of moxifloxacin were between 0.19 and 0.38 μg/ml. The MICs for two strains were higher: ciprofloxacin at 3 and 6 μg/ml, levofloxacin at 1.5 μg/ml, and moxifloxacin at 0.5 and 0.38 μg/ml. These strains presented a mutation at position Asp-91, changing the amino acid to Tyr and Gly, respectively. Three strains presented a mutation at the amino acid codon 87, changing Ser to Val; the MIC of ciprofloxacin was >32 μg/ml, the MIC of levofloxacin was 8 μg/ml, and the MIC of moxifloxacin was 0.75 μg/ml. Finally, the ciprofloxacin and levofloxacin MICs were highest (>32 μg/ml) for the remaining six strains, and the MIC of moxifloxacin remained between 6 and 8 μg/ml. These strains presented a double mutation at positions 87 and 91, with a change from Ser to Phe in the amino acid codon 87 and from Asp to Ala at position 91. The relationships between the MICs and the mutations in target genes are summarized in Tables Tables22 and and33.

TABLE 3.
Relationship between mutations in the QRDRs of the gyrA gene and the MICs for C. striatum

PCR-RFLP of the QRDR of the gyrA gene.

The differences in the QRDR sequence of the gyrA gene between C. amycolatum and C. striatum allow differentiation of these two species by PCR-restriction fragment length polymorphism (RFLP) analysis using the NcoI restriction enzyme. This enzyme has different restriction sites in the sequence of the gyrA gene depending on whether the gyrA sequence belongs to C. striatum or C. amycolatum (Fig. (Fig.22).

FIG. 2.
PCR-RFLP-NcoI analysis of the gyrA gene of C. amycolatum and C. striatum. Lanes 2 and 3, undigested fragments of the QRDR of the gyrA gene of C. amycolatum and C. striatum, respectively; lanes 1 and 4, NcoI-digested fragments of the QRDR of the gyrA gene ...

In both cases three bands were obtained after restriction. In the case of C. striatum the bands had sizes of 37, 126, and 174 bp. The minor band was difficult to see. Meanwhile, the sizes of the bands obtained from the QRDR of the gyrA gene of C. amycolatum were 82, 126, and 129 bp. In this case only two bands were visualized in the agarose gel because the 126- and 129-bp bands were observed as only one.

DISCUSSION

Resistance to quinolones is mainly related to the acquisition of point mutations in the sequence of the QRDR of the gyrA and parC genes, as for most microorganisms, such as, for example, Enterobacteriaceae and gram-positive cocci (13). However, a special group of microorganism, such as Mycobacterium spp., H. pylori, or Campylobacter spp. do not have the parC gene; therefore, resistance is related to the mutations in the gyrA gene (1, 10, 29). In our study, the parC gene of C. striatum and C. amycolatum could not be amplified with degenerate primers. Moreover, using a GenBank search (www.ncbi.nih.nlm.org), the QRDR sequences of the grlA gene of S. aureus and the parC genes of S. pneumoniae and Escherichia coli were compared over the complete genome sequence of C. glutamicum, with no matches being found, and the only sequence matched was the gyrA gene. Therefore, Corynebacterium spp. are other microorganisms belonging to this group of microorganisms, which do not have topoisomerase IV.

The role of mutation(s) in the gyrA gene in the development of quinolone resistance is similar to that of other microorganisms lacking the parC gene in their genome, as in Campylobacter spp. (1, 24) or H. pylori (22, 29). In these microorganisms the mutations in the gene encoding the subunit A of the DNA gyrase can confer quinolone resistance and overexpression of efflux pump(s) may play a complementary role in quinolone resistance acquisition. Overall, the level of quinolone resistance seems to depend on the type of amino acid substitution and on the amino acid substituted. In the case of C. amycolatum only one change in position 87 of GyrA was able to confer resistance to all of the quinolones tested, although with a higher level of resistance to ciprofloxacin than to levofloxacin or moxifloxacin. This is supported by the results obtained with the first-step mutant of C. amycolatum. However, a mutation in the amino acid codon Ser-87 or in the amino acid codon Asp-91 C. striatum only increased the MICs of ciprofloxacin and levofloxacin, whereas the strain remained susceptible to moxifloxacin.

In C. jejuni, one mutation at amino acid codon Asp90 generated a lower MIC than a mutation in the amino acid Thr86 (1). Other microorganisms, lacking the parC gene, such as H. pylori and M. tuberculosis showed the same behavior (15, 29).

In a study by Bachoual et al. (1), C. jejuni mutants resistant in vitro were selected with ciprofloxacin and moxifloxacin. The increase in resistance was related to alterations in the QRDR in the gyrA gene, i.e., a mutation at amino acid position 87 selected in the first-step mutant with ciprofloxacin, changing the amino acid from Ala to Pro. The MICs of both quinolones showed a slight increase, whereas in the second-step mutant a concomitant mutation was found at amino acid position 86 changing Thr to Ile. This new mutation in combination with the previous one resulted in increased resistance, with MICs of 64 μg/ml for ciprofloxacin and 32 μg/ml for moxifloxacin. This is probably what occurred with C. amycolatum, which showed a second mutation in the amino acid codon 88, changing Ala to Pro. This substitution is adjacent to Ser-87, which is the target for the acquisition of resistance. This is a very unusual mutation associated with quinolone resistance, and these concomitant mutations at amino acid codons Ser-87 and Ala-88 could explain the high MICs (>32 μg/ml) observed with all of the quinolones. It is well known that among the 20 coded amino acids proline has a very distinct conformational behavior (2). More precisely, it has a strong tendency to disrupt α-helices. If we take into account that the DNA gyrase quinolone-binding motif, which spans the sequence from Ser-87 to Asp-91, has an α-helical structure (23), our results strongly suggest that a change in Ser-87 to Arg leads Asp-91 to bind the quinolone to the DNA gyrase, whereas the conformational distortion caused by Pro adjacent to Ser-87 leads to no amino acid being involved in DNA gyrase quinolone binding, thereby increasing the MICs of the three quinolones to >32 μg/ml. Second-step quinolone-resistant mutants also showed this second mutation in Ala-88, which was changed to Pro, and is probably the most frequently found in clinical isolates. However, other mutations, such as that affecting Asp-91, can also be obtained in vitro.

The increment in the MIC of ciprofloxacin, which is attributable to the mutation of amino acid codon Ser-87 to Phe in C. striatum, is comparable to the mutations found in Salmonella spp. (11, 12) and Neisseria gonorrhoeae (27, 28), which also consisted of a substitution of Ser to Phe in the amino acid equivalent to Ser-87 of C. striatum. In Salmonella spp., the MIC of ciprofloxacin obtained with Ser to Phe mutation varied from 0.25 to 8 μg/ml (11, 12). Otherwise, for N. gonorrhoeae, the MIC of ciprofloxacin ranged from 0.12 to 1 μg/ml (27, 28). The ranges in MICs may be explained by a concomitant action of one or more efflux pumps.

The activity of new fluoroquinolones against C. striatum and C. amycolatum has rapidly decreased during the last few years. Comparing data from previous studies performed in 1999 and 2001, respectively (18, 20), increases in the MICs at which 50% of the isolates are inhibited of ciprofloxacin from 2 μg/ml for C. amycolatum and from 4 μg/ml for C. striatum to ≥16 μg/ml for both species were observed. This fact may be related to the increase in prescribed fluoroquinolones in Spain during the last few years and to the ability to acquire quinolone resistance.

The difference in the nucleotide sequences of the QRDR of the gyrA gene of C. striatum and C. amycolatum allowed the designing of a PCR-RFLP of the gyrA gene with the restriction enzyme NcoI to differentiate these species. This method is more specific and rapid than the additional tests usually done to differentiate these two species These tests are (i) the morphology test, which shows that the colony is dry with a sugary texture in the case of C. amycolatum and creamy and pale yellow in the case of C. striatum, and (ii) the biochemical test, which consists of the hydrolysis of tyrosine, being positive for C. striatum and negative for C. amycolatum (21). The amplified rDNA restriction analysis (ARDRA) of the 16S gene has also been developed to differentiate Corynebacterium spp. (31) and Acinetobacter spp. (32).

In summary, whereas a mutation in the gyrA gene of C. amycolatum was sufficient to result in high MICs of ciprofloxacin, levofloxacin, and moxifloxacin, two mutations are necessary to result in high MICs of ciprofloxacin and levofloxacin, whereas the moxifloxacin MIC for C. striatum remains lower. Moreover, a rapid PCR-RFLP NcoI of the QRDR of the gyrA gene has been developed to differentiate both species of Corynebacterium. This molecular technique could supplement the phenotypic and biochemical tests currently used to identify these two species correctly.

Acknowledgments

This study was supported in part by grant FIS 02/0353 from the Spanish Ministry of Health and in part by grant 2002 SGR 00121 DURSI (Departament de Universitats Recerca i Societat de l'Informacio) of the Generalitat de Catalunya.

J.M.S. received a grant from the Spanish Society of Infectious Diseases and Clinical Microbiology.

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