Did MRSA emerge before the introduction of methicillin?

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Strains of MRSA may have emerged long before methicillin was introduced into clinical practice, according to new research published in Genome Biology. The study reports that resistance in Staphylococcus aureus may have emerged as a result of widespread use of earlier antibiotics, as opposed to methicillin use.

MRSA was first observed in 1960, less than one year after the introduction of methicillin into clinical practice, and has since been considered a pressing public health issue. The team, including researchers from the University of St. Andrew’s (UK) and the Wellcome Trust Sanger Institute (Cambridge, UK), therefore aimed to uncover the origins of MRSA and its evolutionary history.

First author, Catriona Harkins (University of Dundee, UK) commented: “Within a year of methicillin being first introduced to circumvent penicillin resistance, strains of S. aureus were found that were already resistant to methicillin. In the years that followed resistance spread rapidly in and outside of the UK. Five decades on from the appearance of the first MRSA, multiple MRSA lineages have emerged which have acquired different variants of the resistance gene.”

The researchers sequenced the genomes of 209 historical S. aureus isolates, the oldest of which was identified over 50 years ago. They then applied Bayesian phylogenetic reconstruction in order to infer the time point at which this early MRSA lineage appeared.

The team discovered that S. aureus acquired the gene conferring methicillin resistance, mecA, as early as the 1940s – over 14 years prior to the first clinical use of methicillin. In addition, they observed genes in the historical isolates that conferred resistance to other antibiotics in addition to decreasing susceptibility to disinfectants.

Author, Matthew Holden, from the University of St Andrews, explained: “Our study provides important lessons for future efforts to combat antibiotic resistance. It shows that new drugs which are introduced to circumvent known resistance mechanisms, as methicillin was in 1959, can be rendered ineffective by unrecognized, pre-existing adaptations in the bacterial population. These adaptations happen because – in response to exposure to earlier antibiotics – resistant bacterial strains are selected instead of non-resistant ones as bacteria evolve.”

This study suggests that methicillin may not have been the driving factor in the evolution of MRSA; instead it could have been widespread use of earlier antibiotics such as penicillin. This research highlights how novel drugs could be rendered ineffective by unknown mutations created by the use of other antibiotics.

Holden concluded: “S. aureus has proven to be particularly adept at developing resistance in the face of new antibiotic challenges, rendering many antibiotics ineffective. This remains one of the many challenges in tackling the growing problem of antimicrobial resistance. In order to ensure that future antibiotics retain their effectiveness for as long as possible, it is essential that effective surveillance mechanisms are combined with the use of genome sequencing to scan for the emergence and spread of resistance.”

Sources: Harkins CP, Pichon B, Doumith M et al. Methicillin-resistant Staphylococcus aureus emerged long before the introduction of methicillin into clinical practice. Genome Biol. 18(130) (2017); www.eurekalert.org/pub_releases/2017-07/bc-mey071717.php

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