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 beta-lactam susceptibility

Southon, S. B.; Beres, S. B.; Kachroo, P.; Ojeda Saavedra, M.; Erlendsdottir, H.; Haraldsson, G.; Yerramilli, P.; Pruitt, L.; Zhu, L.; Musser, J. M.; Kristinsson, K. G.

doi:10.1101/2020.05.12.090365

bioRxiv · 10.1101/2020.05.12.090365

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 beta-lactam susceptibility

Southon, S. B.·Beres, S. B.·Kachroo, P.·Ojeda Saavedra, M.·Erlendsdottir, H.·Haraldsson, G.·Yerramilli, P.·Pruitt, L.·Zhu, L.·Musser, J. M.·Kristinsson, K. G.

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Abstract

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 {Phi}29854, {Phi}29862 and {Phi}29661 were deposited in Genbank under accessions ###, ### and ### respectively.

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Southon, S. B., Beres, S. B., Kachroo, P., Ojeda Saavedra, M., Erlendsdottir, H., Haraldsson, G., Yerramilli, P., Pruitt, L., Zhu, L., Musser, J. M., Kristinsson, K. G.. 2020-05-13. 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 beta-lactam susceptibility. https://doi.org/10.1101/2020.05.12.090365

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