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Researchers Find MRSA Genesis Occurred Years Before Clinical Introduction of Methicillin

NEW YORK (GenomeWeb) –  A new study published in Genome Biology found that methicillin-resistant Staphylococcus aureus (MRSA) emerged several years before doctors used methicillin in clinical practice in the late 1950s.

Introduced in 1959 in the UK,  the semi-synthetic beta-lactam antibiotic methicillin was used as an alternative to penicillin due to increasing problems with drug resistance. A pre-emptive screening program of more than 5,000 S. aureus isolates by the Staphylococcus Reference Laboratory in the same year identified MRSA for the first time.

For the new study, scientists from The Wellcome Trust Sanger Institute and Public Health England collaborated with researchers from Denmark, and the US to sequence and analyze the genomes of 209 isolates collected from the UK and Denmark during 1960 to 1989, rebuilding the evolutionary events leading to MRSA's genesis.

The genetic basis of MRSA is linked to a carriage of a mobile cassette of genes known as the staphylococcal cassette chromosome mec element.  

In October 1960, researchers identified three isolates showing increased minimum inhibitory concentrations to methicillin. Within two years, the disease had been identified elsewhere in Europe, with invasive infections identified in Denmark.  

Since then, MRSA has become a chief feature of the international antibiotic resistant landscape. Epidemiological evidence has always suggested the resistance arose around this period, when the mecA gene encoding methicillin resistance carried on the SCCmec element was horizontally transferred to a sensitive strain of S. aureus.

By performing a whole-genome sequence of the first MRSA isolates in Europe between 1960 and 1989, the researchers reconstructed the evolutionary history of the MRSA. They applied Bayesian phylogenetic reconstruction to estimate the point in time where the early MRSA lineage arose and when it acquired the SCCmec gene.

In the population, the researchers found resistance genes and mutations to most of the major classes of antibiotics introduced during the 1950s and 1960s. Among these genes was a mutation in a ribosomal protein RpsL, responsible for resistance to streptomycin, the first aminoglycoside antibiotic. Found in all the archaic MRSA, this mutation was predicted to have appeared around the same time as methicillin resistance.

In an accompanying blog post, the Genome Biology authors noted that "S. aureus is a component of the human microbiota. Therefore the development of streptomycin resistance is likely to have arisen as a collateral consequence of the first use of streptomycin to treat other pathogens such as Mycobacterium tuberculosis."

The results demonstrated that the strain and element's ancestral backgrounds long predated methicillin's introduction into clinical practice, and that MRSA arose 13 years or more before the antibiotic's first usage in the market. Penicillin prescription in the 1940s had the unforeseen effect of driving the emergence of mRSA.

The finding overturned the thought that the widespread usage of methicillin, as well as the selective pressures the drug formed, were the driving forces responsible for methicillin resistance in S. aureus.

Rather, the widespread use of first-generation beta-lactams such as penicillin in the years prior to methicillin's introduction caused the evolution of MRSA.

The results highlight how new drugs, introduced to bypass known resistance mechanisms, can be rendered worthless by adaptations in the bacterial population due to the selective landscape established by the widespread use of other antibiotics. The study also emphasizes the importance of continual surveillance of pathogen populations for evidence of emerging adaptations and resistance patterns in clinical contexts.