Diversity of penicillin-binding protein 2x in Streptococcus pyogenes from England and Wales, 2001 to 2015

Sveikauskaite, G.; Marshall, A. L.; Gorshkova, S.; Guy, R. L.; Wan, Y.; Vieira, A.; Coelho, J.; Moganeradj, K.; Sriskandan, S.; Jauneikaite, E.; Soo, V. W.

doi:10.64898/2026.09.21.752073

bioRxiv · 10.64898/2026.09.21.752073

Diversity of penicillin-binding protein 2x in Streptococcus pyogenes from England and Wales, 2001 to 2015

Sveikauskaite, G.·Marshall, A. L.·Gorshkova, S.·Guy, R. L.·Wan, Y.·Vieira, A.·Coelho, J.·Moganeradj, K.·Sriskandan, S.·Jauneikaite, E.·Soo, V. W.

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Abstract

Streptococcus pyogenes remains clinically susceptible to {beta}-lactam antibiotics, its first-line treatment. Yet recent reports from the US, Iceland, and Japan have identified isolates with PBP2x (a primary {beta}-lactam target) substitutions that reduced antibiotic susceptibility. To determine whether these PBP2x substitutions occurred in S. pyogenes from England and Wales, we re-analysed 2,970 invasive genomes from 2001 to 2015. We found 42 PBP2x sequence mutants in 34% (996/2,970) of the genomes, revealing an unexpected diversity in this antibiotic target. Nine emm12 isolates carried a novel double substitution, PBP2x G600A_P601H, that co-occurred with macrolide resistance genes. Experimentally, these isolates showed 2- to 4-fold elevated minimum inhibitory concentrations for four {beta}-lactam antibiotics, alongside erythromycin resistance. Other PBP2x substitutions, found across seven emm types without reduced antibiotic susceptibility, appeared driven by emm lineage expansion rather than antibiotic pressure. These findings establish a baseline for pbp2x variation, reinforcing the case for sustained genomic surveillance globally.

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Sveikauskaite, G., Marshall, A. L., Gorshkova, S., Guy, R. L., Wan, Y., Vieira, A., Coelho, J., Moganeradj, K., Sriskandan, S., Jauneikaite, E., Soo, V. W.. 2026-09-21. Diversity of penicillin-binding protein 2x in Streptococcus pyogenes from England and Wales, 2001 to 2015. https://doi.org/10.64898/2026.09.21.752073

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