Streptococcus pyogenes pbp2x Mutation Confers Reduced Susceptibility to β-Lactam Antibiotics

Vannice, Kirsten; Ricaldi, Jessica N.; Nanduri, Srinivas; Fang, Ferric C.; Lynch, John B.; Bryson-Cahn, Chloe; Wright, Theodore; Duchin, Jeff; Kay, Meagan; Chochua, Sopio; Beneden, Chris Van; Beall, Bernard

doi:10.1093/cid/ciz1000

Cited by 76 publications

(77 citation statements)

References 11 publications

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“…There were 105 unique amino acid sequence variants of the S. pyogenes PBP2x sequence with no major frameshifts or premature stop codons ( Supplementary File 1 ). We found no instances of the T553K substitution in the PBP2x KSGT motif as reported in the recent S. pyogenes β-lactam resistant isolates (2). Only four S. pyogenes isolate sequences (0.04%) had substitutions within the transpeptidase active site motifs of PBP2x ( Figure 1 and Table 1 ) corresponding to STMK to SAMK and STMK to STIK.…”

Section: Resultssupporting

confidence: 82%

“…Only four isolates contained mutations in the transpeptidase active sites of PBP2x and PBP1a. Although the report of two S. pyogenes isolates with reduced β-lactam susceptibility associated with pbp2x mutations is concerning (2), our findings provide reassurance that these are extremely limited, and perhaps unique, occurrences at this stage. We found a high degree of conservation of GAS PBP2x and PBP1a at transpeptidase active sites and across the broader transpeptidase domains.…”

Section: Discussionsupporting

confidence: 60%

“…Mutations in the penicillin binding proteins (PBPs) have been associated with reduced β-lactam susceptibility for S. pneumoniae (3), S. agalactiae (25), S. dysgalactiae (26), and now S. pyogenes (2). A comparison of PBP2x between β-lactam susceptible reference genomes of S. pyogenes, S. pneumoniae, S. agalactiae , and SDSE demonstrated a high level of inter-species conservation (>72% similarity, Supplementary Figure 1 and Supplementary Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…Streptococcus pyogenes (Group A Streptococcus , GAS) has previously been understood to be uniformly susceptible to β-lactam antibiotics (1). Two S. pyogenes isolates with elevated minimum inhibitory concentrations (MIC) to β-lactam antibiotics have recently been reported (2). Both isolates were molecularly typed as emm 43.4 and had a penicillin binding protein PBP2x missense mutation (T553K) at the transpeptidase active site which was associated with an 8-fold and 3-fold increased MIC to ampicillin and cefotaxime respectively compared to closely related isolates without the PBP2x mutation.…”

Section: Introductionmentioning

confidence: 99%

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Restricted sequence variation in Streptococcus pyogenes penicillin binding proteins

Hayes

Lacey

Morris

et al. 2020

Preprint

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AbstractA recent clinical report has linked Streptococcus pyogenes β-lactam antibiotic resistance to mutations in the Penicillin Binding Protein 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 penicillin binding protein (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 less 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. 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. These 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 nor that mutations are being sequentially acquired in the PBPs.ImportancePenicillin is the first line therapeutic option for Streptococcus pyogenes infections. Despite the global high prevalence of S. pyogenes infections and widespread use of penicillin, reports of resistance to penicillin have been incredibly rare. Recently, penicillin resistance was detected in two clinical S. pyogenes isolates with accompanying mutations in the active site of the penicillin binding protein PBP2x, raising concerns that penicillin resistance may become more widespread. We screened a global database of S. pyogenes genome sequences to investigate the frequency of penicillin binding protein (PBP) mutations, identifying that PBP mutations are uncommon relative to Streptococcus pneumoniae. These findings support clinical observations that penicillin resistance is rare in S. pyogenes, and suggest that there are considerable constraints on S. pyogenes PBP sequence variation.

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Section: Resultssupporting

confidence: 82%

Section: Discussionsupporting

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Restricted sequence variation in Streptococcus pyogenes penicillin binding proteins

Hayes

Lacey

Morris

et al. 2020

Preprint

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“…Beta-lactam antibiotics that inhibit peptidoglycan synthesis are the primary antibacterial treatment for S. pyogenes infections, and despite over 75 years of use, no penicillin-resistant clinical isolate has been reported (10, 11). However, two recent studies reporting reduced in vitro susceptibility to beta-lactam antibiotics among clinical isolates are of concern (12, 13). Macrolides are secondary alternative antibiotics recommended for individuals allergic to penicillin.…”

Section: Introductionmentioning

confidence: 99%

Population genomic molecular epidemiological study of macrolide resistant Streptococcus pyogenes in Iceland, 1995-2016: Identification of a large clonal population with a pbp2x mutation conferring reduced in vitro β-lactam susceptibility

Southon

Beres

Kachroo

et al. 2020

Preprint

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Resistance to macrolide antibiotics is a global concern in the treatment of Streptococcus pyogenes (Group A Streptococcus, GAS) infections. In Iceland, since the detection of the first macrolide-resistant isolate in 1998, three epidemic waves of macrolide-resistant GAS infections have occurred with peaks in 1999, 2004, and 2008. We conducted whole genome sequencing of all 1,575 available GAS macrolide-resistant clinical isolates of all infection types collected at the national reference laboratory in Reykjavik from 1998 to 2016. Among 1,515 erythromycin-resistant isolates, 90.3% were of only three emm types: emm4 (n = 713), emm6 (n = 324), and emm12 (n = 332), with each being predominant in a distinct epidemic peak. The antibiotic efflux pump genes, mef(A) and msr(D), were present on chimeric mobile genetic elements in 99.3% of the macrolide-resistant isolates of these emm types. Of note, in addition to macrolide resistance, virtually all emm12 isolates had a single amino acid substitution in penicillin-binding protein PBP2X that conferred a two-fold increased penicillin G and ampicillin MIC among isolates tested. We conclude that each of the three large epidemic peaks of macrolide-resistant GAS infections occurring in Iceland since 1998 was caused by the emergence and clonal expansion of progenitor strains, with macrolide resistance being conferred predominantly by inducible Mef(A)-Msr(D) drug efflux pumps. The occurrence of emm12 strains with macrolide resistance and decreased beta-lactam susceptibility was unexpected and is of public health concern.RepositoriesGenomic sequencing data for all 1,515 macrolide/erythromycin-resistant isolates were deposited into the National Center for Biotechnology Information Sequence Read Archive under bioproject accession PRJNA614628 and assembled sequences for composite elements Φ29854, Φ29862 and Φ29661 were deposited in Genbank under accessions ###, ### and ### respectively.

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Microbiological Etiology of Necrotizing Soft Tissue Infections

Skrede

Bruun

Rath

et al. 2020

Advances in Experimental Medicine and Biology

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Streptococcus pyogenes pbp2x Mutation Confers Reduced Susceptibility to β-Lactam Antibiotics

Cited by 76 publications

References 11 publications

Restricted sequence variation in Streptococcus pyogenes penicillin binding proteins

Restricted sequence variation in Streptococcus pyogenes penicillin binding proteins

Population genomic molecular epidemiological study of macrolide resistant Streptococcus pyogenes in Iceland, 1995-2016: Identification of a large clonal population with a pbp2x mutation conferring reduced in vitro β-lactam susceptibility

Microbiological Etiology of Necrotizing Soft Tissue Infections

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