Penicillin-Binding Protein Transpeptidase Signatures for Tracking and Predicting β-Lactam Resistance Levels in <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>

ABSTRACT β-Lactam antibiotics are the drugs of choice to treat pneumococcal infections. The spread of β-lactam-resistant pneumococci is a major concern in choosing an effective therapy for patients. Systematically tracking β-lactam resistance could benefit disease surveillance. Here we developed a c...

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Autores principales:	Yuan Li, Benjamin J. Metcalf, Sopio Chochua, Zhongya Li, Robert E. Gertz, Hollis Walker, Paulina A. Hawkins, Theresa Tran, Cynthia G. Whitney, Lesley McGee, Bernard W. Beall
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/f6e11664c4cf436ba1df123fd5c0ad22
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spelling	oai:doaj.org-article:f6e11664c4cf436ba1df123fd5c0ad222021-11-15T15:50:16ZPenicillin-Binding Protein Transpeptidase Signatures for Tracking and Predicting β-Lactam Resistance Levels in <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>10.1128/mBio.00756-162150-7511https://doaj.org/article/f6e11664c4cf436ba1df123fd5c0ad222016-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00756-16https://doaj.org/toc/2150-7511ABSTRACT β-Lactam antibiotics are the drugs of choice to treat pneumococcal infections. The spread of β-lactam-resistant pneumococci is a major concern in choosing an effective therapy for patients. Systematically tracking β-lactam resistance could benefit disease surveillance. Here we developed a classification system in which a pneumococcal isolate is assigned to a “PBP type” based on sequence signatures in the transpeptidase domains (TPDs) of the three critical penicillin-binding proteins (PBPs), PBP1a, PBP2b, and PBP2x. We identified 307 unique PBP types from 2,528 invasive pneumococcal isolates, which had known MICs to six β-lactams based on broth microdilution. We found that increased β-lactam MICs strongly correlated with PBP types containing divergent TPD sequences. The PBP type explained 94 to 99% of variation in MICs both before and after accounting for genomic backgrounds defined by multilocus sequence typing, indicating that genomic backgrounds made little independent contribution to β-lactam MICs at the population level. We further developed and evaluated predictive models of MICs based on PBP type. Compared to microdilution MICs, MICs predicted by PBP type showed essential agreement (MICs agree within 1 dilution) of >98%, category agreement (interpretive results agree) of >94%, a major discrepancy (sensitive isolate predicted as resistant) rate of <3%, and a very major discrepancy (resistant isolate predicted as sensitive) rate of <2% for all six β-lactams. Thus, the PBP transpeptidase signatures are robust indicators of MICs to different β-lactam antibiotics in clinical pneumococcal isolates and serve as an accurate alternative to phenotypic susceptibility testing. IMPORTANCE The human pathogen Streptococcus pneumoniae is a leading cause of morbidity and mortality worldwide. β-Lactam antibiotics such as penicillin and ceftriaxone are the drugs of choice to treat pneumococcal infections. Some pneumococcal strains have developed β-lactam resistance through altering their penicillin-binding proteins (PBPs) and have become a major concern in choosing effective patient therapy. To systematically track and predict β-lactam resistance, we obtained the sequence signatures of PBPs from a large collection of clinical pneumococcal isolates using whole-genome sequencing data and found that these “PBP types” were predictive of resistance levels. Our findings can benefit the current era of strain surveillance when whole-genome sequencing data often lacks detailed resistance information. Using PBP positions that we found are always substituted within highly resistant strains may lead to further refinements. Sequence-based predictions are accurate and may lead to the ability to extract critical resistance information from nonculturable clinical specimens.Yuan LiBenjamin J. MetcalfSopio ChochuaZhongya LiRobert E. GertzHollis WalkerPaulina A. HawkinsTheresa TranCynthia G. WhitneyLesley McGeeBernard W. BeallAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 3 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Yuan Li Benjamin J. Metcalf Sopio Chochua Zhongya Li Robert E. Gertz Hollis Walker Paulina A. Hawkins Theresa Tran Cynthia G. Whitney Lesley McGee Bernard W. Beall Penicillin-Binding Protein Transpeptidase Signatures for Tracking and Predicting β-Lactam Resistance Levels in <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>
description	ABSTRACT β-Lactam antibiotics are the drugs of choice to treat pneumococcal infections. The spread of β-lactam-resistant pneumococci is a major concern in choosing an effective therapy for patients. Systematically tracking β-lactam resistance could benefit disease surveillance. Here we developed a classification system in which a pneumococcal isolate is assigned to a “PBP type” based on sequence signatures in the transpeptidase domains (TPDs) of the three critical penicillin-binding proteins (PBPs), PBP1a, PBP2b, and PBP2x. We identified 307 unique PBP types from 2,528 invasive pneumococcal isolates, which had known MICs to six β-lactams based on broth microdilution. We found that increased β-lactam MICs strongly correlated with PBP types containing divergent TPD sequences. The PBP type explained 94 to 99% of variation in MICs both before and after accounting for genomic backgrounds defined by multilocus sequence typing, indicating that genomic backgrounds made little independent contribution to β-lactam MICs at the population level. We further developed and evaluated predictive models of MICs based on PBP type. Compared to microdilution MICs, MICs predicted by PBP type showed essential agreement (MICs agree within 1 dilution) of >98%, category agreement (interpretive results agree) of >94%, a major discrepancy (sensitive isolate predicted as resistant) rate of <3%, and a very major discrepancy (resistant isolate predicted as sensitive) rate of <2% for all six β-lactams. Thus, the PBP transpeptidase signatures are robust indicators of MICs to different β-lactam antibiotics in clinical pneumococcal isolates and serve as an accurate alternative to phenotypic susceptibility testing. IMPORTANCE The human pathogen Streptococcus pneumoniae is a leading cause of morbidity and mortality worldwide. β-Lactam antibiotics such as penicillin and ceftriaxone are the drugs of choice to treat pneumococcal infections. Some pneumococcal strains have developed β-lactam resistance through altering their penicillin-binding proteins (PBPs) and have become a major concern in choosing effective patient therapy. To systematically track and predict β-lactam resistance, we obtained the sequence signatures of PBPs from a large collection of clinical pneumococcal isolates using whole-genome sequencing data and found that these “PBP types” were predictive of resistance levels. Our findings can benefit the current era of strain surveillance when whole-genome sequencing data often lacks detailed resistance information. Using PBP positions that we found are always substituted within highly resistant strains may lead to further refinements. Sequence-based predictions are accurate and may lead to the ability to extract critical resistance information from nonculturable clinical specimens.
format	article
author	Yuan Li Benjamin J. Metcalf Sopio Chochua Zhongya Li Robert E. Gertz Hollis Walker Paulina A. Hawkins Theresa Tran Cynthia G. Whitney Lesley McGee Bernard W. Beall
author_facet	Yuan Li Benjamin J. Metcalf Sopio Chochua Zhongya Li Robert E. Gertz Hollis Walker Paulina A. Hawkins Theresa Tran Cynthia G. Whitney Lesley McGee Bernard W. Beall
author_sort	Yuan Li
title	Penicillin-Binding Protein Transpeptidase Signatures for Tracking and Predicting β-Lactam Resistance Levels in <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>
title_short	Penicillin-Binding Protein Transpeptidase Signatures for Tracking and Predicting β-Lactam Resistance Levels in <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>
title_full	Penicillin-Binding Protein Transpeptidase Signatures for Tracking and Predicting β-Lactam Resistance Levels in <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>
title_fullStr	Penicillin-Binding Protein Transpeptidase Signatures for Tracking and Predicting β-Lactam Resistance Levels in <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>
title_full_unstemmed	Penicillin-Binding Protein Transpeptidase Signatures for Tracking and Predicting β-Lactam Resistance Levels in <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>
title_sort	penicillin-binding protein transpeptidase signatures for tracking and predicting β-lactam resistance levels in <named-content content-type="genus-species">streptococcus pneumoniae</named-content>
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/f6e11664c4cf436ba1df123fd5c0ad22
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Penicillin-Binding Protein Transpeptidase Signatures for Tracking and Predicting β-Lactam Resistance Levels in <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>

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