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A close homologue of the mecA gene, the primary drug resistance determinant in methicillin resistant Staphylococcus aureus (MRSA), is ubiquitous in the animal commensal species Staphylococcus sciuri, yet most isolates of this staphylococcal species are susceptible to β-lactam antibiotics including methicillin. Recently, we showed that in a methicillin-resistant mutant of S. sciuri prepared in the laboratory, the mecA homologue is converted to an antibiotic resistance gene by a point mutation introduced into the –10 consensus of the promoter and such promoter-up mutants of the S. sciuri mecA can express a significant degree of methicillin resistance when introduced into an antibiotic-susceptible strain of S. aureus. We now demonstrate that in this system further increase of the drug resistance phenotype may be achieved under antibiotic pressure by at least two different mechanisms. The first one of these involves the introduction of a point mutation at nucleotide Nt1889 in the coding region of the S. sciuri-derived mecA determinant, resulting in the replacement of an asparagine with a threonine residue downstream of the conserved SXXK motif which causes extensive reduction in the β-lactam antibiotic binding capacity (affinity) of the penicillin binding protein (PBP) encoded by the S. sciuri mecA homologue. A second, distinct, mechanism causing increased methicillin resistance is associated with mutation(s) of unknown nature in the genetic background of the S. aureus host.