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Antimicrobial Agents and Chemotherapy, December 2003, p. 3877-3880, Vol. 47, No. 12
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.12.3877-3880.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Acquired Macrolide Resistance Genes in Pathogenic Neisseria spp. Isolated between 1940 and 1987

Sydney Cousin Jr.,1 William L. H. Whittington,2 and Marilyn C. Roberts1*

Departments of Pathobiology,1 Medicine,University of Washington, Seattle, Washington 981952

Received 21 July 2003/ Returned for modification 26 August 2003/ Accepted 12 September 2003


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ABSTRACT
 
Seventy-six Neisseria gonorrhoeae isolates, isolated between 1940 and 1987, and seven Neisseria meningitidis isolates, isolated between 1963 and 1987, were screened for the presence of acquired mef(A), erm(B), erm(C), and erm(F) genes by using DNA-DNA hybridization, PCR analysis, and sequencing. The mef(A), erm(B), and erm(F) genes were all identified in a 1955 N. gonorrhoeae isolate, while the erm(C) gene was identified in a 1963 N. gonorrhoeae isolate. Similarly, both the mef(A) and erm(F) genes were identified in a 1963 N. meningitidis isolate. All four acquired genes were found in later isolates of both species. The mef(A) gene from a 1975 N. gonorrhoeae isolate was sequenced and had 100% DNA and amino acid identity with the mef(A) gene from a 1990s Streptococcus pneumoniae isolate. Selected early isolates were able to transfer their acquired genes to an Enterococcus faecalis recipient, suggesting that these genes are associated with conjugative transposons. These isolates are the oldest of any species to carry the mef(A) gene and among the oldest to carry these erm genes.


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INTRODUCTION
 
Erythromycin, the prototype macrolide antibiotic, was introduced over 50 years ago. Macrolide use has increased during the past decade, after introduction of the semisynthetic erythromycin derivatives clarithromycin and azithromycin. These compounds are used extensively to treat community-acquired pneumonia and chlamydial infection (4, 12). Although erythromycin and azithromycin, in the 1-g dose, are not recommended for treatment of gonococcal infection, azithromycin has been used in some parts of the world to treat gonorrhea (7, 30). Increased gonococcal resistance to erythromycin has been noted since the 1960s (19), and resistance to azithromycin has been recently identified (7, 13). Gonococcal resistance to erythromycin has been linked to resistance to killing by fecal lipids, and such resistant strains are more likely to be recovered from men who have sex with men than from heterosexual men (9).

Macrolide resistance in most gram-positive and gram-negative bacteria is often due to the acquisition of rRNA methylase genes. Thirty-one of these genes, which add one or two methyl groups to a specific adenine (A2058 in Escherichia coli) in the 23S rRNA (23), have been identified. It has been shown that some recently recovered Neisseria gonorrhoeae and commensal Neisseria spp. carry, individually or in combination, the erm(B), erm(C), or erm(F) gene (6, 21). These genes are associated with conjugative transposons that can be transferred to both gram-negative and gram-positive recipients and often code for other antibiotic-resistant genes (3, 14, 15, 21, 23). The earliest known isolates of organisms other than Neisseria spp. that carry erm gene(s) were originally recovered in the 1950s (2, 3). More recently, macrolide resistance due to active efflux encoded by the mef(A) gene has been described (5, 15, 16, 24-27). This gene has also been found in recent gonococcal and commensal Neisseria spp. isolates (14).

Finding two different types of acquired genes in recently isolated gonococci led us to question how long the erm and mef(A) genes have been present in N. gonorrhoeae and if these genes could also be found in the related pathogen Neisseria meningitidis. Also, we examined the promoter region of the mtr(R) gene for sequence changes in the 13-bp repeat, since the loss of an adenine has been shown to alter macrolide susceptibilities in N. gonorrhoeae (29, 30), though recently mutations in the 23S rRNA have also been found to change macrolide susceptibility (18). Thus, the study examined three genotypes, acquired erm(B), erm(C), erm(F), and mef(A) genes, and changes in the sequence in the promoter region of the mtr(R) in 76 N. gonorrhoeae isolates isolated between 1940 and 1987 and 7 N. meningitidis isolates isolated between 1963 and 1987 by using DNA-DNA hybridization, PCR analysis, and sequencing.


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MATERIALS AND METHODS
 
Bacterial strains. The isolates (n = 76) were reconstituted from lyophilized ampoules and from stocks frozen at -70°C and included 7 strains isolated from 1940 to 1969 (Denmark, 5; United States, 1; and Ethiopia, 1), 26 from 1970 to 1979 (England, Singapore, Asia, Belgium, Kenya, New Zealand, and the United States), and 43 from 1980 to 1987 (United States). Twenty-one isolates carrying ß-lactamase plasmids and 16 isolates carrying a tet(M) plasmid (20, 22) were included. Seven N. meningitidis isolates (United States, 6; and Denmark, 1) from 1963 to 1987 were studied. The identity of the isolates was confirmed, and susceptibilities to erythromycin, azithromycin, penicillin, and tetracycline were determined for each species by using methods recommended by the National Committee for Clinical Laboratory Standards (NCCLS) (17) on samples of 37 of the gonococcal isolates and all 7 N. meningitidis isolates.

Detection of acquired genes. The isolates were initially screened by using DNA-DNA hybridization of whole-cell dot blots and/or DNA dot blots, as previously described (6, 14, 21). The presence of all genes was confirmed by PCR assays, as previously described (14, 16, 21). The primers used are listed in Table 1.


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  		TABLE 1. Primers used for PCR and DNA-DNA hybridization studies

Sequencing. The mef(A) gene from a 1975 N. gonorrhoeae isolate was sequenced as previously described (6, 14). The mef(A) sequence was compared to sequences from Streptococcus pneumoniae (GenBank accession no. U83667) and S. pneumoniae Tn1207.1 (GenBank accession no. AF227520) by using Genetics Computer Group software (University of Wisconsin, Madison). The GenBank accession no. for the N. gonorrhoeae mef(A) gene is AY319932.

Analysis of mtr(R) region. A 380-bp PCR fragment which included the promoter region of the mtr(R) genes was amplified and sequenced as previously described by using a GenBank sequence (accession no. Z25796) to represent the wild type (6). The isolates were grouped as wild type, loss of an adenine, or other, which included other variations of sequences in this region (6, 13, 29, 30).

Conjugation experiments. Donors included the 1963 N. meningitidis isolate and three N. gonorrhoeae isolates from the 1970s recovered from various geographic locations. The recipient was the erythromycin-susceptible Enterococcus faecalis strain JH2-2, for which the MIC is <0.5 µg/ml. Matings were performed on agar plates, and transconjugants were identified as previously described (14, 21). The transconjugants were selected on 5 or 10 µg of erythromycin/ml (14, 15). The presence of acquired erm and/or mef genes was determined by DNA-DNA hybridization and PCR. Erythromycin MICs for selected transconjugants were determined by using standard NCCLS protocols for agar dilution susceptibility (17).

Analyses. The Kruskal-Wallis test was utilized to assess the relationship between acquired erythromycin resistance genes and erythromycin susceptibilities.


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RESULTS
 
Distribution of the acquired genes. Among the isolates from 1940 through 1969, one 1955 Danish isolate carried the erm(B), erm(F), and mef(A) genes; a second Danish strain from 1963 carried the erm(C) gene; and a 1960s United States isolate carried the mef(A) gene (Table 2). All seven isolates from this time period had wild-type mtr(R) promoter 13-bp inverted repeat sequences.


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  		TABLE 2. Acquired genes and variability in mtr(R) promoter region

Among 26 isolates from the 1970s, 13 (50%) did not carry any of the four acquired genes examined. Nine (35%) isolates carried one of the four genes, three (12%) carried two of the genes, and one (4%) carried three of the acquired genes (Table 2). One isolate had a deletion at position A2058 (delA2058), also described as -A (13, 18, 29). The other isolates (96%) carried wild-type sequences in the mtr(R) promoter region.

Of the 43 isolates from the 1980s, 32 (74%) carried no acquired genes, 8 carried a single acquired gene, 3 carried two genes, and 1 carried three genes. In this group, 32 (74%) carried a wild-type mtr(R) promoter sequence, 8 (17%) had an adenine deletion, and 3 (7%) carried other changes in the 13-bp inverted repeat region.

Four (57%) of the seven N. meningitidis isolates carried acquired genes, one carried mef(A) and a single erm gene, two carried one or more erm genes alone, and one carried mef(A) alone. Both mef(A) and erm(F) were identified in a Danish strain (NRL 5041) isolated in 1963. Two of the these seven isolates had wild-type 13-bp mtr(R) sequences, and the remaining five strains had three base pair differences from the wild-type sequence that had previously been described when the genome of N. meningitidis serogroup A strain Z2491 was sequenced (25).

Among gonococci tested for antimicrobial susceptibility, 12 of 37 isolates carried a single acquired resistance gene and 5 carried multiple acquired genes. None of these 37 isolates had mutations in the mtr(R) promoter region. The geometric mean MIC for strains carrying the erm(B) gene was 1.0 µg/ml, compared to a geometric mean of 0.31 µg/ml for all other strains (P, 0.04). The carriage of erm(C) (MIC, 0.71 µg/ml versus 0.31 µg/ml), erm(F) (MIC, 0.51 µg/ml versus 0.31 µg/ml), or mef(A) (MIC, 0.38 µg/ml versus 0.33 µg/ml) was not significantly associated with decreased gonococcal susceptibility to erythromycin. The limited number of N. meningitidis strains did not permit analysis of the effect of the carriage of acquired genes on antimicrobial susceptibilities.

mef(A) sequence. There was 100% identity at the nucleotide and amino acid level between the mef(A) gene from a 1975 gonococcal isolate from the United States and that from S. pneumoniae U83667. In contrast, there was only 90% identity with the mef(A) gene from S. pneumoniae Tn1207.1 AF227520 (data not shown).

Conjugal transfer studies. The donors were three N. gonorrhoeae isolates from the 1970s carrying erm(F) plus mef(A) or the erm(F) or mef(A) gene alone and one 1963 N. meningitidis isolate carrying erm(F) plus mef(A). From 3.2 x 10-7 to 5.4 x 10-8 macrolide resistance genes per recipient were transferred to E. faecalis JH2-2 organisms from each of the four donors examined. The N. gonorrhoeae and N. meningitidis strains carrying both erm(F) and mef(A) genes transferred each gene separately at similar frequencies (the number of transconjugants carrying one versus the other acquired gene was indistinguishable).

The MIC of erythromycin was determined for selected transconjugants carrying the erm or mef(A) genes from matings with each of three different donors. The MIC for all the transconjugants was >64 µg/ml, while the MIC for the parental E. faecalis strain was <0.5 µg/ml.


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DISCUSSION
 
erm(A), erm(B), erm(C), and erm(F) genes from a 1950s Bacteroides thetaiotaomicron isolate, an erm(F) gene from a 1950s Bacteroides fragilis isolate (3), and an erm(B) gene from a 1950s enterococcus isolate (2) have previously been identified. The mef(A) gene has been identified in Streptococcus pyogenes and S. pneumoniae strains isolated in the 1990s (5, 26, 27) and in viridans group streptococci isolated between 1988 and 1995 (1). In this study, the earliest strains identified with acquired genes included a 1955 N. gonorrhoeae strain carrying erm(B), erm(F), and mef(A) genes, a 1963 N. gonorrhoeae strain carrying an erm(C) gene, and a 1963 N. meningitidis strain carrying both erm(F) and mef(A) genes. These isolates are the oldest identified to date that carry the mef(A) gene and are among the oldest isolates to carry the erm(B), erm(F), and erm(C) genes. All the transconjugants were selected on erythromycin with a concentration that was at least 10-fold higher than the MIC for the recipient. The MIC of erythromycin for all of the transconjugants tested was >64 µg/ml, clearly suggesting that the erm and mef(A) genes are able to confer erythromycin resistance to the transconjugants. Differences in susceptibilities of the transconjugants carrying the mef(A) versus the erm gene were not observed, though this may be evident at higher concentrations of erythromycin than those we tested.

The mef(A) gene from a 1975 isolate was sequenced and had 100% amino acid identity with the mef(A) gene from a S. pneumoniae strain isolated in the 1990s. This S. pneumoniae strain also carried the orf3 to orf8 genes, most of which have unknown functions, though they have been found in conjugative transposon Tn5252 and have previously been described in Tn1207.1 (24). This finding suggests that this type of element has been in the nonstreptococcal population for at least 20 years prior to its identification and study in streptococci in the 1990s.

In streptococci, carriage of the mef(A) gene confers a lower level of resistance to erythromycin than does carriage of the erm(B) gene (16), but these differences have not always been found (14, 15). Therefore, it was not unexpected that the MICs for the transconjugants carrying the mef(A) gene were indistinguishable from those for strains not carrying the mef(A) gene. However, the number of strains studied was small, and the sample was not meant to represent the gonococcal population. Additionally, because of the small sample size we were unable to control for the effects of other resistance determinants, such as chromosomal mutations, that have been shown to influence macrolide susceptibilities (8). The influence of these acquired genes on macrolide susceptibilities awaits larger studies of isolates selected in an unbiased way.

Previously, N. meningitidis strains have been used as recipients (14);however, this is the first time that N. meningitidis has been shown to transfer both erm and mef(A) genes to a recipient, suggesting that these genes were functional in the genus and associated with mobile elements for 40 to 50 years. In addition, the 1970s N. gonorrhoeae strains were able to act as donors for both erm(F) and mef(A) genes, indicating their presence on mobile elements. It has previously been demonstrated that Bacteroides conjugative chromosomal elements, such as Tcr Emr DOT, Tcr Emr 12256, and Tcr Emr CEST, which contain both erm(F) and the tet(Q) genes, are able to mobilize Bacteroides nonconjugative plasmids in cis (11, 28). More recently, it has been shown that the mef(A) gene in S. pyogenes is linked upstream with tet(O), which encodes a ribosomal protection tetracycline resistance protein highly related to the Tet(M) protein found in Neisseria spp. This linkage allows both the tet(O) and the mef(A) genes to be transferred as a single unit, and for the first time the tet(O) gene can be moved between chromosomes of different species and genera (10). Given the potential that these mobile elements present in influencing movement of themselves and other antibiotic resistance genes, it will be of interest to learn if these elements have had an impact on, or could impact, the evolution of pathogenic Neisseria in this time of increasing antibiotic use of macrolides.


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ACKNOWLEDGMENTS
 
This study was supported in part by NIH grant A131448. S.C. was supported by NIH training grant AI07140.


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FOOTNOTES
 
* Corresponding author. Mailing address: Department of Pathobiology, Box 357238, School of Public Health and Community Medicine, University of Washington, Seattle, WA 98195-7238. Phone: (206) 543-8001. Fax: (206) 543-3873. E-mail: marilynr{at}u.washington.edu. Back


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Antimicrobial Agents and Chemotherapy, December 2003, p. 3877-3880, Vol. 47, No. 12
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.12.3877-3880.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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