MECHANISMS OF METHICILLIN RESISTANCE IN STAPHYLOCOCCI

The continuously high prevalence of methicillin-resistant staphylococc i (MRS) throughout the world is a constant threat to public health, ow ing to the multiresistant characteristics of these bacteria. Methicill in resistance is phenotypically associated with the presence of the pe nicillin-binding protein 2a (PBP2a) not present in susceptible staphyl ococci. This protein has a low binding affinity for beta-lactam antibi otics. IL is a transpeptidase which may take over cell wall synthesis during antibiotic treatment when normally occurring PBPs are inactivat ed by ligating beta-lactams. PBP2a is encoded by the mecA gene, which is located in mec, a foreign DNA region. Expression of PBP2a is regula ted by proteins encoded by the plasmid-borne blaR1-blaI inducer-repres sor system and the corresponding genomic mecR1-mecI system. The blaR1- blaI products are important both for the regulation of beta-lactamase and for mecA expression. Methicillin resistance is influenced by a num ber of additional factors, e.g. the products of the chromosomal fem ge nes which are important in the synthesis of normal peptidoglycan precu rsor molecules. Inactivation of fem-genes results in structurally defi cient precursors which are not accepted as cell wall building blocks b y the ligating PBP2a transpeptidase during antibiotic treatment. This may result in reduced resistance to beta-lactam antibiotics. Inactivat ion of genes affecting autolysis has shown that autolytic enzymes are also of importance in the expression of methicillin resistance. Methic illin resistance has evolved among earth microorganisms for protection against exogenous or endogenous antibiotics. Presumably the mec regio n was originally transferred from coagulase negative staphylococci (CN S) to Staphylococcus aureus (SA). A single or a few events of this kin d with little subsequent interspecies transfer had been anticipated. H owever, recent data suggest a continuous horizontal acquisition by S. aureus of mec, being unidirectional from CNS to SA. Methicillin resist ance may also be associated with mechanisms independent of mecA, resul ting in borderline methicillin resistance. These mechanisms include be ta-lactamase hyperproduction, production of methicillinases, acquisiti on of structurally modified normal PBPs, or the appearance of small co lony variants of SA. Most MRS are multiresistant, and the mec region m ay harbour several resistance determinants, resulting in a clustering of resistance genes within this region.