According to a new study published in the journal Genome Biology, methicillin use was not the original driving factor in the evolution of methicillin-resistant Staphylococcus aureus (MRSA) as previously thought; rather it was the widespread use of first generation antibiotics such as penicillin in the years prior to the introduction of methicillin.
This digitally-colorized scanning electron microscopic (SEM) image depicts a number of mustard-colored, spheroid-shaped Staphylococcus aureus bacteria that were in the process of escaping their destruction by blue-colored human white blood cells. Magnification – 20,000x. Image credit: National Institute of Allergy and Infectious Diseases.
“Our study provides important lessons for future efforts to combat antibiotic resistance,” said lead author Professor Matthew Holden, a molecular microbiologist at the University of St Andrews.
“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.”
Professor Holden and co-authors found that Staphylococcus aureus acquired the mecA gene — a gene that confers methicillin resistance by producing a protein called penicillin-binding protein 2a (PBP2a) — as early as the mid-1940s, about 14 years before the first use of methicillin.
The introduction of penicillin in the 1940s led to the selection of Staphylococcus aureus strains that carried this gene.
“Within a year of methicillin being first introduced to circumvent penicillin resistance, strains of Staphylococcus aureus were found that were already resistant to methicillin,” said study first author Dr. Catriona Harkins, clinical lecturer in dermatology at the University of Dundee.
“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.”
To uncover the origins of the very first MRSA and to trace its evolutionary history, the team sequenced the genomes of a unique collection of 209 of the earliest MRSA isolates recovered in Europe between 1960 and 1989.
The authors also found genes in these isolates that confer resistance to numerous other antibiotics, as well as genes associated with decreased susceptibility to disinfectants.
“Staphylococcus aureus has proven to be particularly adept at developing resistance in the face of new antibiotic challenges, rendering many antibiotics ineffective,” Professor Holden said.
“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.”
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Catriona P. Harkins et al. 2017. Methicillin-resistant Staphylococcus aureus emerged long before the introduction of methicillin into clinical practice. Genome Biology 18 (130); doi: 10.1186/s13059-017-1252-9
