New mechanism for methicillin resistance in Staphylococcus aureus: clinical isolates that lack the PBP 2a gene and contain normal penicillin-binding proteins with modified penicillin-binding capacity

Abstract

Seventeen clinical isolates of Staphylococcus aureus (from the United States and Europe) selected for low (borderline)-level methicillin resistance (MIC of methicillin, 2 to 4 micrograms/ml; MIC of oxacillin, 0.5 to 8 micrograms/ml) were examined for their mechanisms of resistance. Five strains were typical of heterogeneous S. aureus: they gave positive reactions with a DNA probe specific for mec and contained a small fraction (10(-6] of highly resistant cells (MIC, greater than 100 micrograms/ml). The rest of the 12 strains were homogeneous with respect to their methicillin resistance: the MIC of methicillin for all cells was 2 to 4 micrograms/ml, and no cells for which MICs were 50 micrograms/ml or higher were detectable (less than 10(-9]. None of these strains reacted with the mec-specific DNA probe. One representative strain of each group was characterized in more detail. Strain CDC-1, prototype of heterogeneous methicillin-resistant S. aureus, contained penicillin-binding protein (PBP) 2a; its DNA could transform a methicillin-susceptible and novobiocin-resistant recipient to methicillin resistance with ca. 35% linkage to Novr. Introduction of the "factor X" determinant (K. Murakami and A. Tomasz, J. Bacteriol. 171:874-879, 1989) converted strain CDC-1 to high, homogeneous resistance. Strain CDC-6, prototype of the second group of isolates, showed completely homogeneous MICs of methicillin, oxacillin, and cefotaxime. The strain contained modified "normal" PBPs: PBPs 1 and 2 showed low drug reactivity (and/or cellular amounts), and PBP 4 was present in elevated amounts. No PBP 2a could be detected. DNA isolated from strain CDC-6 could transform the methicillin-susceptible and novobiocin-resistant strain to methicillin resistance in a multistep fashion, but this resistance showed no genetic linkage to the Nov marker. We suggest that staphylococci with borderline resistance may contain at least three different classes of mechanism: heterogeneous, methicillin-resistant S. aureus, PBPs of modified drug reactivities, and the previously reported hyperproduction of beta-lactamase (L.K. McDougal and C. Thornsberry, J. Clin Microbiol. 23:832-839, 1986).

FemABX Peptidyl Transferases: a Link between Branched-Chain Cell Wall Peptide Formation and β-Lactam Resistance in Gram-Positive Cocci

“…Clinical S. aureus isolates with such mutations have been identified and have been termed MODSA in reference to their modified PBPs (106). Furthermore, a decreased affinity of PBP3 for ␤-lactams was found to lead to low-level methicillin resistance in Staphylococcus epidermidis (78).…”

Antimicrobial susceptibility profile and research of mec A and erm genes in coagulase-negative staphylococci isolated from platelet concentrates bags

“…This mecC gene has also been reported in CoNS as Staphylococcus stepanovicii, Staphylococcus xylosus and Staphylcoccus scirui (Harrison et al, 2013a(Harrison et al, , 2013bLoncaric et al, 2013). As already suggested for the mecA gene, we can probably infer that the origin of the mecC gene is also among the CoNS (Tsubakishita et al, 2010;Couto et al, 2013). Although mecC gene detection is rare and reported only in Europe so far, this gene is a potential diagnosis problem and triggers several issues for future studies (Paterson, Harrison, Holmes, 2014).…”

“…This less frequent resistance, however, may also be due to the beta-lactamase overproduction by oxacillin inactivation, resulting in partial hydrolysis of the beta-lactamase ring (borderline resistance to methicillin -BORSA) or the presence of a PBP with low affinity to oxacillin (MODSA) (Tomasz et al, 1989;Ito et al, 2003;Rossi, Andreazzi, 2005). In these last two resistance mechanisms to methicillin, bacteria do not carry the mecA gene (Mohanasoundaram, Lalitha, 2008).…”

Molecular Epidemiology of Methicillin-Resistant Staphylococcus aureus in Finland

“…Low-level methicillin resistance can result from the production of large amounts of betalactamases, or increased production and/or modified penicillin-binding capacity of normal PBPs (168,269). Such borderline resistant S. aureus strains (BORSA) seldom have minimal inhibitory concentrations (MIC) of methicillin exceeding 16 µg/ml, and their clinical significance is thought to be limited.…”