AbstractThe evolutionary histories of the antibiotic-resistant Streptococcus pneumoniae lineages PMEN3 and PMEN9 were reconstructed using global collections of genomes. In PMEN3, one resistant clade spread worldwide, and underwent 25 serotype switches, enabling evasion of vaccine-induced immunity. In PMEN9, only 9 switches were detected, and multiple resistant lineages emerged independently and circulated locally. In Germany, PMEN9s expansion correlated significantly with the macrolide:penicillin consumption ratio. These isolates were penicillin sensitive but macrolide resistant, through a homologous recombination that integrated Tn1207.1 into a competence gene, preventing further diversification via transformation. Analysis of a species-wide dataset found 183 acquisitions of macrolide resistance, and multiple gains of the tetracycline-resistant transposon Tn916, through homologous recombination, often originating in other streptococcal species. Consequently, antibiotic selection preserves atypical recom- bination events that cause sequence divergence and structural variation throughout the S. pneumoniae chromosome. These events reveal the genetic exchanges between species normally counter-selected until perturbed by clinical interventions.

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