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Chapter 28 : Multiple Stages in the Evolution of Methicillin-Resistant Staphylococcus aureus
Category: Fungi and Fungal Pathogenesis; Bacterial Pathogenesis
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The appearance of methicillin-resistant Staphylococcus aureus (MRSA) represents a fascinating detective story of evolution in multiple stages beginning with the original source of the resistant gene mecA followed by its mobilization and association with the unique staphylococcal chromosomal cassettes (SCC), which appear to have their own independent evolutionary history. In this chapter the authors have concentrated on the stages of this evolutionary process that are relatively rarely discussed in reviews. A DNA probe generated from the S. aureus mecA sequence was used to search for a staphylococcal species in which all epidemiologically unrelated isolates produced a hybridizing signal under stringent conditions even if the isolates were susceptible to methicillin. The high-level methicillin resistance of the S. aureus transductants had an absolute dependence on the S. sciuri gene. The evolution of the mecA gene may have occurred on a much longer timescale and under the selective pressure of penicillin in a staphylococcal species such as S. sciuri, which appears to be free of the penicillinase plasmid. Ongoing studies in several laboratories of structural variants of SCCmec in various staphylococcal strains should eventually shed some light on the stages of molecular evolution between the original source of mecA and the construction of an SCC vector capable of capturing and delivering the chromosomal mecA determinant to an S. aureus recipient. Characterization of MRSA clones by molecular and microbiological techniques indicates that the evolution of MRSA does not stop after the acquisition of the SCCmec determinant.
Amino acid sequence of the putative transpeptidase domains of mecA from S. aureus and the mecA of S. sciuri. Reproduced from Wu et al., 1996, with permission.
(A) Dependence of the methicillin-resistant phenotype on the presence of mecA in the bacteria. S. aureus mutant RU4 was transduced to high-level methicillin resistance either by the introduction of the S. sciuri mecA on plasmid pSTW8 (containing the mecA from S. sciuri K1M200) to generate transductant SS1 (●) or by the introduction of the S. aureus mecA on plasmid pSTW2C (containing the mecA from strain COL) to generate transductant SS2 (■). Loss of the plasmid-borne mecA constructs in the cured cells SS*1(○) and SS*2 (□) resulted in loss of resistance. (B) S. sciuri mecA catalyzes the production of S. aureus–type peptidoglycan in methicillin-resistant transductants of S. aureus. Strains were grown from small inocula in the presence of the following concentrations of methicillin: S. sciuri K1M200 (20 μg/ml), S. aureus strain COL (20 μg/ml), and S. aureus transductants SS1(5 μg/ml) and SS2 (20 μg/ml). Muropeptide hydrolysates were analyzed by high-pressure liquid chromatography. (Reproduced with permission from Severin et al., 2005.)
Multidrug resistance of the first European MRSA. Sequential appearance of methicillin-susceptible and methicillin-resistant blood isolates of S. aureus belonging to phage group III and the related 83A complex (in Denmark). (■), P-S-T-M isolates; (♦), P-S-T isolates. The numbers plotted represent all S. aureus blood isolates identified in Denmark during the particular year. (Reproduced with permission from Crisostomo et al., 2001.)
The rise and fall of phage group III and 83A complex in Denmark. SAB, S. aureus bacteremia. (Adapted with permission from Westh et al., 1992.)
Gradual resurgence of MRSA in Denmark after the year 2000. (Adapted with permission from DANMAP, 2006.)
Sequential replacement of MRSA clones in Portuguese hospitals. (Adapted with permission from Aires de Sousa and de Lencastre, 2004.)
Genetic backgrounds of future MRSA clones present in Denmark among MSSA clones in the period 1957 to 1973