{'fraction_non_alphanumeric': 0.031427716252618976, 'fraction_numerical': 0.005686920083807243, 'mean_word_length': 5.778904665314402, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Classic Spotlight: Molecular Biology of Methicillin Resistance in Staphylococcus aureus

Staphylococcus aureus colonizes the nares of about 30% of the human population (1). Carriers are at higher risk for staphylococcal skin and soft tissue infections, pneumonia, osteomyelitis, and bacteremia and represent a reservoir for S. aureus spread. Introduction of penicillin, the first antibiotic of the emerging class of -lactam compounds, into clinical practice in the early to mid1940s was associated with dramatic improvements in the outcome of staphylococcal disease. However, within a few years of extensive therapeutic use of penicillin, S. aureus penicillin resistance was encountered, first in hospitals and then also in the community (2). Resistant strains produced penicillinase to inactivate penicillin. To address penicillin resistance, Beecham introduced the first semisynthetic -lactam, methicillin, which cannot be cleaved by penicillinase and cured infections with penicillin-resistant S. aureus. Again, within a few years of clinical use of such agents, strains resistant to semisynthetic -lactams emerged in hospitals and eventually also in the community (2). These isolates, designated methicillin-resistant S. aureus (MRSA), were resistant to penicillin, methicillin, and other -lactams, including cephalosporins and carbapenems. Of note, resistance no longer involved enzymatic cleavage of the antibiotics. Barry Hartman and Alexander Tomasz provided an important insight into the methicillin resistance mechanism. In a classic Journal of Bacteriology (JB) paper (3), these authors used [H]benzylpenicillin labeling experiments with isogenic pairs of methicillin-sensitive and methicillin-resistant strains to identify a low-affinity penicillin-binding protein, designated PBP2a, uniformly associated with resistant isolates. Identification of the corresponding gene and resistance mechanism proved difficult, as many different genes of MRSA contribute to -lactam resistance (4). Another classic JB paper elegantly solved this puzzle, taking advantage of an earlier observation that in some MRSA isolates genetic traits for -lactam resistance and aminoglycoside resistance are closely linked (5). Using the MRSA determinant for tobramycin resistance in Escherichia coli as probe, Michio Matsuhashi and colleagues cloned S. aureus DNA adjacent to the tobramycin resistance gene to isolate the determinant for PBP2a (PBP2=) expression. Competitive inhibition experiments with -lactams and [H]benzylpenicillin as well as V8-protease digestion patterns revealed the identity of native and cloned PBP2a. The corresponding gene, mecA, encodes a transpeptidase for peptidoglycan synthesis that cannot be blocked by -lactam antibiotics (6). These classic JB papers laid the foundations for our current understanding of antibiotic resistance in S. aureus: mecA is located on a mobile cassette element, staphylococcal cassette chromosome mec (SCCmec), providing resistance against many different antibiotics and enabling the rapid evolution of drug resistance as new strains evolve in community or hospital settings (2). Nonetheless, the MRSA pandemic, the global threat of antibiotic-resistant S. aureus producing clinical outcomes reminiscent of the preantibiotic era, must still be addressed by fundamental research on this microbe.