5. Genes mediating resistance to MLS B antibiotics
5.3. Enzymatic inactivation
Enzymes inactivating specific members of the MLSB antibiotics have been found for all the different classes or even substances of this group.134 This pool of enzymes comprises hydrolases, transferases, esterases and phosphorylases. Enzymes, that are acting on the antimicrobial agents of interest – the macrolides and the lincosamides – and that are present in staphylococci are summarized in the following section.134
Macrolide phosphotransferase and esterases. Enzymes that inactivate macrolides have been mainly detected in Enterobacteriaceae rather than in Gram-positive cocci.134,182 Enzymes which have also been observed in staphylococci are a macrolide phosphotransferase and two esterases.
The mph(C) (macrolide phosphotransferase) gene has been described in staphylococci only in close linkage to msr(A)96 and together with erm(Y) on the plasmid pMS97.95,96 The Mph(C) enzyme appears to modify only 14-membered macrolides effectively.95
The function of an esterase has been described for S. aureus.182 The substrates which are hydrolyzed by the staphylococcal protein differ from those hydrolyzed by the enzymes of E. coli. The esterases of E. coli, Ere(A) and Ere(B) (erythromycin esterification), inactivate 14- and 15-membered macrolides, whereas 14- and 16-membered macrolides serve as substrates for the Gram-positive esterase.182 The genetic basis of this enzyme was not determined in that study. Homology to the esterase genes in E. coli is likely, because the GC content and the codon usage of these genes imply a Gram-positive origin.84,182 Recently, the genes ere(A) and ere(B) was detected in S. aureus isolates of human origin.142,144
Lincosamide nucleotidyltransferase. Inactivation of lincomycin has been reported for staphylococci of animal origin in the 1980s.82 However, the genetic background of the resistance phenotype was first determined in human strains of S. haemolyticus82 and S. aureus.14 The responsible gene is lnu(A) (lincosamides nucleotidyltransferase; originally designated linA, linA’ and linA-like).84 The product of this gene is a lincosamide O-nucleotidyltransferase.81 This protein inactivates lincomycin and clindamycin, although staphylococcal isolates remain apparently susceptible to the latter antimicrobial agent.14,81,82
This phenomenon is thought to depend on the relatively higher affinity of clindamycin to the staphylococcal ribosome.4
The lnu(A) gene was detected on small plasmids14,82 in several staphylococcal species from different sources.34,81,123 The first complete sequence of a lnu(A)-carrying plasmid was published recently.91 The sequenced plasmid, pBMSa1, originated from a Mexican S. aureus isolated from a case of bovine subclinical mastitis.91 The plasmid structure and functional analysis classified pBMSa1 as a RC plasmid.91
Two further lnu genes have been detected in Gram-positive bacteria, lnu(B)13 and lnu(C).4 Both genes are present mainly in Gram-positive cocci other than staphylococci. The lnu(B) gene was detected in an E. faecium isolate.13 The lnu(C) gene was isolated from a S. agalactiae isolate.4 Both enzymes showed the phenomenon observed for lnu(A): In the natural Gram-positive host they conferred phenotypic resistance to lincomycin only, although they can also inactivate clindamycin in a cell-free system.
Aim of this study
The aim of this study was to investigate the molecular basis of resistance to MLSB
antibiotics with particular reference to the lincosamide pirlimycin. Pirlimycin is exclusively licensed for therapeutical use in subclinical mastitis in dairy cattle caused by Gram-positive cocci. Among this group of bacteria CoNS have been of special interest, since only few data on these important mastitis pathogens are currently available. No comprehensive studies on bovine CoNS have been done so far which investigated a sufficiently large number of isolates for their MLSB resistance phenotypes and genotypes.
To fill this gap, 298 CoNS isolates from bovine subclinical mastitis have been collected and comparatively investigated. They were differentiated to the species level. Their susceptibility to pirlimycin and erythromycin as well as to comparator antimicrobial agents commonly used in mastitis therapy was determined. In isolates resistant to erythromycin and/or pirlimycin the corresponding resistance genes were identified [Chapter 2].
Beside their role in mastitis, CoNS are likely to serve as a reservoir for resistance genes to other bacteria – also including more pathogenic species. Plasmids are of major importance in the resistance transfer among staphylococci. Two groups of plasmids – two novel types of erm(C)-carrying plasmids [Chapter 3, Chapter 4] and a group of lnu(A)-carrying plasmids [Chapter 5] – were completely sequenced and analyzed to gain insight into their evolution and their impact on the spreading of these resistance genes.
Pirlimycin cannot induce the expression of the inducibly regulated resistance gene erm(C). In consideration of previous in vitro as well as in vivo studies on other non-inducers, it was assumed that constitutively expressed resistant mutants will develop under the selective pressure of pirlimycin. To confirm this assumption, the ability of pirlimycin – in comparison to the 16-membered macrolides spiramycin and tylosin – to select for constitutively resistant mutants was studied in an in vitro assay [Chapter 6].
In addition, coagulase-positive staphylococcal and streptococcal isolates derived from different animal sources during the large-scale resistance monitoring program BfT-GermVet were investigated for their MLSB resistance pheno- and genotype [Chapter 7] to detect a potential association of certain resistance genes to distinct bacterial species as well as to specific animal origins.
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