Genetic Elements Responsible for Erythromycin Resistance in Streptococci

Abstract

During the last two decades, growing rates of erythromycin resistance have been reported in many countries among both Streptococcus pyogenes (29) and Streptococcus pneumoniae (63) clinical isolates. This trend was partly due to a further spread of the conventional methylase-mediated target site modification mechanism of resistance, but to an even greater extent it reflected the emergence of an active efflux-mediated mechanism of erythromycin resistance. Besides less common mutations in 23S rRNA or ribosomal proteins, target site modification consists in posttranscriptional methylation of an adenine residue in 23S rRNA; this is caused by erm class gene-encoded methylases and usually results in coresistance to macrolide, lincosamide, and streptogramin B antibiotics (MLS phenotype) (62, 63). The traditional and widely predominant erm determinant in streptococci, erm(B), can be expressed either constitutively or inducibly and is usually associated with high-level resistance (62). A more recently described methylase gene, erm(TR) (92), an erm(A) subclass (84), is normally inducible (46, 55) and is widely distributed in S. pyogenes isolates (55, 58), whose resistance level appears to depend on the contribution of a drug efflux pump (51). erm(TR) has been detected in other beta-hemolytic Streptococcus species (59, 67, 110), whereas it is quite uncommon in S. pneumoniae (12, 34, 41, 43, 97, 106). erm(T), characterized by a very low G+C content (ca. 25%), was detected in inducibly erythromycin-resistant isolates of group D streptococci in Taiwan (99) and subsequently in the United States (40). Very recently, it has been detected in U.S. invasive isolates of inducibly resistant S. pyogenes that were negative for conventional erythromycin resistance determinants (111). Efflux-mediated erythromycin resistance is associated, in streptococci, with a low-level resistance pattern affecting, among MLS antibiotics, only 14- and 15-membered macrolides (M phenotype) (96). Active efflux is encoded by mef-class genes, which include several variants. mef(A), the first mef gene to be discovered, was originally described in S. pyogenes (22) and was subsequently found to be widespread in this species, but it is also common in S. pneumoniae and other streptococcal species (60). mef(E), detected in S. pneumoniae shortly afterward (98), was found in a variety of other Streptococcus species (60), although it has only exceptionally been reported in S. pyogenes (4, 6, 87). Less common mef genes have been detected in S. pneumoniae [mef(I) (28)] and S. pyogenes [mef(O) (87)], and mef(B) and mef(G) new alleles have recently been described in group B (15) and group G (5, 15) beta-hemolytic streptococci, respectively. An msr class gene with homology to msr(A)—an ATP-binding cassette gene associated with macrolide efflux in Staphylococcus aureus (85)—is located immediately downstream of the mef gene. This msr gene is usually designated msr(D), even though different variants are associated with different mef genes. Studies carried out in pneumococci demonstrated that mef and msr(D) are cotranscribed, suggesting that the proteins encoded by the two genes may act as a dual efflux system (48), inducible by erythromycin (3). It has also been suggested that the msr(D)-encoded pump is capable of functioning independently of the one encoded by mef (3, 33). Macrolide inactivation due to a phosphotransferase encoded by the mph(B) gene, formerly described only in gram-negative bacteria, has lately been detected in Streptococcus uberis, where the inactivation mechanism, however, conferred only resistance to spiramycin (1). Until a decade ago, knowledge about the genetic elements responsible for erythromycin resistance in streptococci was virtually confined to a few plasmids or transposons carrying erm(B), then called ermAM or simply erm (56, 65). Such transposons mainly included Tn917, detected in Enterococcus faecalis when it was still regarded as a Streptococcus species (94, 101, 102), and Tn1545, detected in S. pneumoniae and also encoding resistance, besides tetracycline, to erythromycin and kanamycin (31, 32). Remarkably, Tn1545 was related to Tn916 (47), the prototype of a family of broad-host-range conjugative transposons conferring tetracycline resistance via the tet(M) gene (24, 81). Other Tn916-related erm(B)-carrying transposons early described in Streptococcus species (81) ceased to be reported in later studies. During the last decade, the discovery of the above-mentioned variety of erythromycin resistance genes in streptococci has been closely followed by the identification and characterization of a variety of genetic elements responsible for the resistance and its possible spread via intra- and interspecific transfer. Different erythromycin resistance genes are carried by different elements: in the case of mef genes, such close gene-element association was a major argument for recommending that mef(A), mef(E), and any future mef variants continue to be discriminated and kept apart (60) as opposed to being collected in a single class, mef(A), due to their high degree of similarity (84). This minireview is aimed at presenting such new knowledge about the genetic elements responsible for erythromycin resistance in streptococci. Elements and their essential characteristics are summarized in Table ​Table11. TABLE 1. Essential characteristics of established genetic elements responsible for erythromycin resistance in streptococci