TY - JOUR
T1 - Evidence for the evolutionary steps leading to mecA-mediated β-lactam resistance in staphylococci
AU - Araujo Rolo Mateus, Joana Rita Gonçalves
AU - Worning, Peder
AU - Boye Nielsen, Jesper
AU - Sobral, Rita
AU - Bowden, Rory
AU - Bouchami, Ons
AU - Damborg, Peter
AU - Guardabassi, Luca
AU - Perreten, Vincent
AU - Westh, Henrik
AU - Tomasz, Alexander
AU - de Lencastre, Hermínia
AU - Miragaia, Maria
N1 - This work was financially supported by: Project LISBOA-01-0145-FEDER-007660 (Microbiologia Molecular, Estrutural e Celular) funded by Fundo Europeu de Desenvolvimento Regional through COMPETE2020 - Programa Operacional Competitividade e Internacionaliza??o and by national funds through Funda??o para a Ci?ncia e a Tecnologia; Project UID/Multi/04378/2013 (Unidade de Ci?ncias Biomoleculares Aplicadas-UCIBIO), funded by national funds from Funda??o para a Ci?ncia e a Tecnologia and co-financed by the European Regional Development Fund under the PT2020 Partnership Agreement (POCI-01-0145-FEDER-007728); project PTDC/BIA-EVF/117507/2010 and PTDC/FIS-NAN/0117/2014 from Funda??o para a Ci?ncia e a Tecnologia; European Society of Clinical Microbiology and Infectious Diseases Research Grants 2010, awarded to MM; and US Public Health Service Award R01-AI457838-15, awarded to AT. JR was supported by fellowship SFRH / BD / 72675 / 2010 from Funda??o para a Ci?ncia e a Tecnologia and grant FEMS-RG-2014-0078 from the Federation of European Microbiology Societies. The authors acknowledge Dr. Kloos for the unrestricted gift of the great majority of the S. sciuri isolates that were used in this study. In addition, we thank Dr. Ivo Sedl?cek, Dr. Oto Melter and Dr. Jos? Melo-Cristino for providing some of the S. sciuri strains that are part of this study and Dr. Engeline van Duijkeren from the National Institute for Public Health and the Environment (RIVM, Denmark) for providing the strains S. fleurettii 402567 and S. vitulinus 401946. We additionally thank Dr. Isabel Couto for the initial characterization of S. sciuri strains.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - The epidemiologically most important mechanism of antibiotic resistance in Staphylococcus aureus is associated with mecA–an acquired gene encoding an extra penicillin-binding protein (PBP2a) with low affinity to virtually all β-lactams. The introduction of mecA into the S. aureus chromosome has led to the emergence of methicillin-resistant S. aureus (MRSA) pandemics, responsible for high rates of mortality worldwide. Nonetheless, little is known regarding the origin and evolution of mecA. Different mecA homologues have been identified in species belonging to the Staphylococcus sciuri group representing the most primitive staphylococci. In this study we aimed to identify evolutionary steps linking these mecA precursors to the β-lactam resistance gene mecA and the resistance phenotype. We sequenced genomes of 106 S. sciuri, S. vitulinus and S. fleurettii strains and determined their oxacillin susceptibility profiles. Single-nucleotide polymorphism (SNP) analysis of the core genome was performed to assess the genetic relatedness of the isolates. Phylogenetic analysis of the mecA gene homologues and promoters was achieved through nucleotide/amino acid sequence alignments and mutation rates were estimated using a Bayesian analysis. Furthermore, the predicted structure of mecA homologue-encoded PBPs of oxacillin-susceptible and -resistant strains were compared. We showed for the first time that oxacillin resistance in the S. sciuri group has emerged multiple times and by a variety of different mechanisms. Development of resistance occurred through several steps including structural diversification of the non-binding domain of native PBPs; changes in the promoters of mecA homologues; acquisition of SCCmec and adaptation of the bacterial genetic background. Moreover, our results suggest that it was exposure to β-lactams in human-created environments that has driven evolution of native PBPs towards a resistance determinant. The evolution of β-lactam resistance in staphylococci highlights the numerous resources available to bacteria to adapt to the selective pressure of antibiotics.
AB - The epidemiologically most important mechanism of antibiotic resistance in Staphylococcus aureus is associated with mecA–an acquired gene encoding an extra penicillin-binding protein (PBP2a) with low affinity to virtually all β-lactams. The introduction of mecA into the S. aureus chromosome has led to the emergence of methicillin-resistant S. aureus (MRSA) pandemics, responsible for high rates of mortality worldwide. Nonetheless, little is known regarding the origin and evolution of mecA. Different mecA homologues have been identified in species belonging to the Staphylococcus sciuri group representing the most primitive staphylococci. In this study we aimed to identify evolutionary steps linking these mecA precursors to the β-lactam resistance gene mecA and the resistance phenotype. We sequenced genomes of 106 S. sciuri, S. vitulinus and S. fleurettii strains and determined their oxacillin susceptibility profiles. Single-nucleotide polymorphism (SNP) analysis of the core genome was performed to assess the genetic relatedness of the isolates. Phylogenetic analysis of the mecA gene homologues and promoters was achieved through nucleotide/amino acid sequence alignments and mutation rates were estimated using a Bayesian analysis. Furthermore, the predicted structure of mecA homologue-encoded PBPs of oxacillin-susceptible and -resistant strains were compared. We showed for the first time that oxacillin resistance in the S. sciuri group has emerged multiple times and by a variety of different mechanisms. Development of resistance occurred through several steps including structural diversification of the non-binding domain of native PBPs; changes in the promoters of mecA homologues; acquisition of SCCmec and adaptation of the bacterial genetic background. Moreover, our results suggest that it was exposure to β-lactams in human-created environments that has driven evolution of native PBPs towards a resistance determinant. The evolution of β-lactam resistance in staphylococci highlights the numerous resources available to bacteria to adapt to the selective pressure of antibiotics.
UR - http://www.scopus.com/inward/record.url?scp=85018372872&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1006674
DO - 10.1371/journal.pgen.1006674
M3 - Article
C2 - 28394942
AN - SCOPUS:85018372872
SN - 1553-7390
VL - 13
JO - PLoS Genetics
JF - PLoS Genetics
IS - 4
M1 - e1006674
ER -