Restricted Sequence Variation in <named-content content-type="genus-species">Streptococcus pyogenes</named-content> Penicillin Binding Proteins

ABSTRACT A recent clinical report has linked Streptococcus pyogenes β-lactam antibiotic resistance to mutation in the penicillin binding protein (PBP) PBP2x. To determine whether this is an isolated case or reflects a broader prevalence of mutations that might confer reduced β-lactam susceptibility,...

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Autores principales: Andrew Hayes, Jake A. Lacey, Jacqueline M. Morris, Mark R. Davies, Steven Y. C. Tong
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Publicado: American Society for Microbiology 2020
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spelling oai:doaj.org-article:33272d6b2bc74c76b1c99e71b5d93a432021-11-15T15:29:16ZRestricted Sequence Variation in <named-content content-type="genus-species">Streptococcus pyogenes</named-content> Penicillin Binding Proteins10.1128/mSphere.00090-202379-5042https://doaj.org/article/33272d6b2bc74c76b1c99e71b5d93a432020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00090-20https://doaj.org/toc/2379-5042ABSTRACT A recent clinical report has linked Streptococcus pyogenes β-lactam antibiotic resistance to mutation in the penicillin binding protein (PBP) PBP2x. To determine whether this is an isolated case or reflects a broader prevalence of mutations that might confer reduced β-lactam susceptibility, we investigated the relative frequency of PBP sequence variation within a global database of 9,667 S. pyogenes isolates. We found that mutations in S. pyogenes PBPs (PBP2x, PBP1a, PBP1b, and PBP2a) occur infrequently across this global database, with fewer than 3 amino acid changes differing between >99% of the global population. Only 4 of the 9,667 strains contained mutations near transpeptidase active sites of PBP2x or PBP1a. The reported PBP2x T553K substitution was not identified. These findings are in contrast to those of 2,520 S. pneumococcus sequences where PBP mutations are relatively frequent and are often located in key β-lactam binding pockets. These data, combined with the general lack of penicillin resistance reported in S. pyogenes worldwide, suggests that extensive, unknown constraints restrict S. pyogenes PBP sequence plasticity. Our findings imply that while heavy antibiotic pressure may select for mutations in the PBPs, there is currently no evidence of such mutations becoming fixed in the S. pyogenes population or that mutations are being sequentially acquired in the PBPs. IMPORTANCE β-Lactam antibiotics are the first-line therapeutic option for Streptococcus pyogenes infections. Despite the global high prevalence of S. pyogenes infections and widespread use of β-lactams worldwide, reports of resistance to β-lactam antibiotics, such as penicillin, have been incredibly rare. Recently, β-lactam resistance, as defined by clinical breakpoints, was detected in two clinical S. pyogenes isolates with accompanying mutations in the active site of the penicillin binding protein PBP2x, raising concerns that β-lactam resistance will become more widespread. We screened a global database of S. pyogenes genome sequences to investigate the frequency of PBP mutations, identifying that PBP mutations are uncommon relative to those of Streptococcus pneumoniae. These findings support clinical observations that β-lactam resistance is rare in S. pyogenes and suggest that there are considerable constraints on S. pyogenes PBP sequence variation.Andrew HayesJake A. LaceyJacqueline M. MorrisMark R. DaviesSteven Y. C. TongAmerican Society for MicrobiologyarticleStreptococcus pyogenesbeta-lactamspenicillin resistancepenicillin binding proteinsMicrobiologyQR1-502ENmSphere, Vol 5, Iss 2 (2020)
institution DOAJ
collection DOAJ
language EN
topic Streptococcus pyogenes
beta-lactams
penicillin resistance
penicillin binding proteins
Microbiology
QR1-502
spellingShingle Streptococcus pyogenes
beta-lactams
penicillin resistance
penicillin binding proteins
Microbiology
QR1-502
Andrew Hayes
Jake A. Lacey
Jacqueline M. Morris
Mark R. Davies
Steven Y. C. Tong
Restricted Sequence Variation in <named-content content-type="genus-species">Streptococcus pyogenes</named-content> Penicillin Binding Proteins
description ABSTRACT A recent clinical report has linked Streptococcus pyogenes β-lactam antibiotic resistance to mutation in the penicillin binding protein (PBP) PBP2x. To determine whether this is an isolated case or reflects a broader prevalence of mutations that might confer reduced β-lactam susceptibility, we investigated the relative frequency of PBP sequence variation within a global database of 9,667 S. pyogenes isolates. We found that mutations in S. pyogenes PBPs (PBP2x, PBP1a, PBP1b, and PBP2a) occur infrequently across this global database, with fewer than 3 amino acid changes differing between >99% of the global population. Only 4 of the 9,667 strains contained mutations near transpeptidase active sites of PBP2x or PBP1a. The reported PBP2x T553K substitution was not identified. These findings are in contrast to those of 2,520 S. pneumococcus sequences where PBP mutations are relatively frequent and are often located in key β-lactam binding pockets. These data, combined with the general lack of penicillin resistance reported in S. pyogenes worldwide, suggests that extensive, unknown constraints restrict S. pyogenes PBP sequence plasticity. Our findings imply that while heavy antibiotic pressure may select for mutations in the PBPs, there is currently no evidence of such mutations becoming fixed in the S. pyogenes population or that mutations are being sequentially acquired in the PBPs. IMPORTANCE β-Lactam antibiotics are the first-line therapeutic option for Streptococcus pyogenes infections. Despite the global high prevalence of S. pyogenes infections and widespread use of β-lactams worldwide, reports of resistance to β-lactam antibiotics, such as penicillin, have been incredibly rare. Recently, β-lactam resistance, as defined by clinical breakpoints, was detected in two clinical S. pyogenes isolates with accompanying mutations in the active site of the penicillin binding protein PBP2x, raising concerns that β-lactam resistance will become more widespread. We screened a global database of S. pyogenes genome sequences to investigate the frequency of PBP mutations, identifying that PBP mutations are uncommon relative to those of Streptococcus pneumoniae. These findings support clinical observations that β-lactam resistance is rare in S. pyogenes and suggest that there are considerable constraints on S. pyogenes PBP sequence variation.
format article
author Andrew Hayes
Jake A. Lacey
Jacqueline M. Morris
Mark R. Davies
Steven Y. C. Tong
author_facet Andrew Hayes
Jake A. Lacey
Jacqueline M. Morris
Mark R. Davies
Steven Y. C. Tong
author_sort Andrew Hayes
title Restricted Sequence Variation in <named-content content-type="genus-species">Streptococcus pyogenes</named-content> Penicillin Binding Proteins
title_short Restricted Sequence Variation in <named-content content-type="genus-species">Streptococcus pyogenes</named-content> Penicillin Binding Proteins
title_full Restricted Sequence Variation in <named-content content-type="genus-species">Streptococcus pyogenes</named-content> Penicillin Binding Proteins
title_fullStr Restricted Sequence Variation in <named-content content-type="genus-species">Streptococcus pyogenes</named-content> Penicillin Binding Proteins
title_full_unstemmed Restricted Sequence Variation in <named-content content-type="genus-species">Streptococcus pyogenes</named-content> Penicillin Binding Proteins
title_sort restricted sequence variation in <named-content content-type="genus-species">streptococcus pyogenes</named-content> penicillin binding proteins
publisher American Society for Microbiology
publishDate 2020
url https://doaj.org/article/33272d6b2bc74c76b1c99e71b5d93a43
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