Methicillin-resistant Staphylococcus aureus emerged long before the introduction of methicillin into clinical practice

TY - JOUR

T1 - Methicillin-resistant Staphylococcus aureus emerged long before the introduction of methicillin into clinical practice

AU - Harkins, Catriona P

AU - Pichon, Bruno

AU - Doumith, Michel

AU - Parkhill, Julian

AU - Westh, Henrik

AU - Tomasz, Alexander

AU - de Lencastre, Herminia

AU - Bentley, Stephen D

AU - Kearns, Angela M

AU - Holden, Matthew T G

PY - 2017/7/20

Y1 - 2017/7/20

N2 - BACKGROUND: The spread of drug-resistant bacterial pathogens poses a major threat to global health. It is widely recognised that the widespread use of antibiotics has generated selective pressures that have driven the emergence of resistant strains. Methicillin-resistant Staphylococcus aureus (MRSA) was first observed in 1960, less than one year after the introduction of this second generation beta-lactam antibiotic into clinical practice. Epidemiological evidence has always suggested that resistance arose around this period, when the mecA gene encoding methicillin resistance carried on an SCCmec element, was horizontally transferred to an intrinsically sensitive strain of S. aureus.RESULTS: Whole genome sequencing a collection of the first MRSA isolates allows us to reconstruct the evolutionary history of the archetypal MRSA. We apply Bayesian phylogenetic reconstruction to infer the time point at which this early MRSA lineage arose and when SCCmec was acquired. MRSA emerged in the mid-1940s, following the acquisition of an ancestral type I SCCmec element, some 14 years before the first therapeutic use of methicillin.CONCLUSIONS: Methicillin use was not the original driving factor in the evolution of MRSA as previously thought. Rather it was the widespread use of first generation beta-lactams such as penicillin in the years prior to the introduction of methicillin, which selected for S. aureus strains carrying the mecA determinant. Crucially this highlights how new drugs, introduced to circumvent known resistance mechanisms, can be rendered ineffective by unrecognised adaptations in the bacterial population due to the historic selective landscape created by the widespread use of other antibiotics.

AB - BACKGROUND: The spread of drug-resistant bacterial pathogens poses a major threat to global health. It is widely recognised that the widespread use of antibiotics has generated selective pressures that have driven the emergence of resistant strains. Methicillin-resistant Staphylococcus aureus (MRSA) was first observed in 1960, less than one year after the introduction of this second generation beta-lactam antibiotic into clinical practice. Epidemiological evidence has always suggested that resistance arose around this period, when the mecA gene encoding methicillin resistance carried on an SCCmec element, was horizontally transferred to an intrinsically sensitive strain of S. aureus.RESULTS: Whole genome sequencing a collection of the first MRSA isolates allows us to reconstruct the evolutionary history of the archetypal MRSA. We apply Bayesian phylogenetic reconstruction to infer the time point at which this early MRSA lineage arose and when SCCmec was acquired. MRSA emerged in the mid-1940s, following the acquisition of an ancestral type I SCCmec element, some 14 years before the first therapeutic use of methicillin.CONCLUSIONS: Methicillin use was not the original driving factor in the evolution of MRSA as previously thought. Rather it was the widespread use of first generation beta-lactams such as penicillin in the years prior to the introduction of methicillin, which selected for S. aureus strains carrying the mecA determinant. Crucially this highlights how new drugs, introduced to circumvent known resistance mechanisms, can be rendered ineffective by unrecognised adaptations in the bacterial population due to the historic selective landscape created by the widespread use of other antibiotics.

KW - Bacterial Proteins/genetics

KW - Bayes Theorem

KW - Drug Resistance, Bacterial/genetics

KW - Evolution, Molecular

KW - History, 20th Century

KW - Humans

KW - Methicillin/history

KW - Methicillin-Resistant Staphylococcus aureus/drug effects

KW - Penicillin-Binding Proteins/genetics

KW - Phylogeny

KW - Whole Genome Sequencing

U2 - 10.1186/s13059-017-1252-9

DO - 10.1186/s13059-017-1252-9

M3 - Journal article

C2 - 28724393

SN - 1474-7596

VL - 18

JO - Genome Biology (Online Edition)

JF - Genome Biology (Online Edition)

M1 - 130

ER -