Horizontal transmission of penicillin binding protein 1A caused a nationwide spread of β-lactam resistance in pneumococci

The emergence and spread of drug-resistant bacteria continue to be a global crisis. The mechanism of the resistance spread via mobile genetic elements such as plasmids is well known, however, the impact of the natural transformation on the spread remains unclear. Streptococcus pneumoniae is well known to be a transformable pathogen by natural competence and they become {beta}-lactam resistance by the acquisition of chromosomal genetic elements including mutated PBPs by natural transformation. To trace the transmission of pneumococcal PBPs among nationwide pediatric population and analyze the impact of transformed PBPs to {beta}-lactam resistance, we collected and analyzed more than 1300 isolates of S. pneumoniae through nationwide surveillance study for pediatric pneumococcal diseases between 2012-2017 in Japan. We discovered a high prevalence of a specific PBP1A type (pbp1a-13) in {beta}-lactam resistant pneumococci that had a 370SSMK substitution in their {beta}-lactam binding SXXK motif, suggesting that this pbp1a-13 transferred horizontally between different clones resulting in emergence and spread of {beta}-lactam resistant pneumococcal clones. Divergence dating analysis suggested that pbp1a-13 was inserted into major resistant lineages in the early 1990s through the 2000s, before introduction of pneumococcal conjugate vaccines in Japan. Our additional analysis for pneumococcal isolates that were recovered in the 90s in Japan suggested that pbp1a-13 in GPSC1 (serotype 19F-CC236) and GPSC14 (serotype 23F-CC242) isolates were the origin of the currently spread pbp1a-13. We provide evidence of pbp1a horizontal transmission at a nationwide scale and highlight the importance of PBP profile monitoring for identifying the emergence and spread of resistant pneumococci lineages.