Widespread Pbp2x Mutations Reduce S Pyogenes Beta-lactam Susceptibility

Streptococcus pyogenes strains with mutations in the pbp2x gene may have decreased susceptibility to beta-lactam antibiotics.

Streptococcus pyogenes strains with mutations in the pbp2x gene may have decreased susceptibility to beta-lactam antibiotics and may be geographically widespread, according to a study recently published in the Journal of Clinical Microbiology.

Although there are more than 700 million annual cases of S pyogenes (group A streptococcus; GAS) globally, the universal susceptibility of GAS infections to beta-lactam antimicrobial agents is fortunate and well known in the infectious disease field. However, an outbreak investigation has been recently reported reduced susceptibility in 2 related S pyogenes strains to the antibiotics commonly used to treat these infections, including ampicillin, amoxicillin, and cefotaxime. Further investigation found that these 2 strains had the same amino-acid substituting/nonsynonymous mutation in the pbp2x gene, which encodes the penicillin-binding protein 2X (PBP2X). Since beta-lactams are the global front-line treatment for the majority of GAS infections, this discovery could signal a substantial public health problem. Therefore, this study examined a library of 7025 S pyogenes genome sequences to assess the potential broader extent of this alarming discovery.

In total, 7025 S. pyogenes genome sequences of type emm1 (n=3615) emm28 (n=2095), and emm89 (n=1315) clinical isolates form intercontinental sources were analyzed for nonsynonymous mutations in pbp2x via bioinformatic analysis.

Results suggest that amino acid-altering mutations in pbp2x that were associated with small decreases in beta-lactam susceptibility are more widespread than previously thought. Of the analyzed strains, none of the mutations identified showed in vitro resistance to any of the 6 beta-lactams studied and none approached the MIC levels for ampicillin or cefotaxime. However, 137 strains were identified with 37 amino acid changes at 36 sites in the 2259-nucelotide pbp2x gene that could alter MIC values for beta-lactam antibiotics.

 This elevated percentage of nonsynonymous mutations suggests the effect of positive selection acting on the pbp2x gene. Each of the 137 strains had only 1 amino acid replacement relative to the wild-type PBP2X sequence, with 1 exception in an emm28 strain that was recovered from the United States that had 2 contiguous amino acid replacements.

Further, there were 4 sites that were identified that had the same amino acid replacement present in multiple emm types and that were present among multiple isolates within a single emm type, which strongly suggests that these changes have been selected by beta-lactam antibiotic exposure.

Additionally, phylogenetic analysis showed that strains of the same emm type with the identical amino acid replacement were closely related and most likely a descent from a common progenitor, with 1 exception. These results serve as evidence that these organisms can successfully disseminate to new human hosts and cause infections with altered phenotypes (ie, enhanced virulence or increased antimicrobial agent resistance/decreased beta-lactam susceptibility).

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Taken together, these findings highlight the importance of renewed efforts to monitor antimicrobial susceptibility rates and values in this pathogen on an ongoing basis and the need for expanded vaccine efforts to formulate an efficacious human vaccine against S. pyogenes. Overall, the study authors conclude that, “Enhanced surveillance and further epidemiological and molecular genetic study of this potential emergent antimicrobial problem are warranted.”


Musser JM, Beres SB, Zhu L, et al. Reduced susceptibility of streptococcus pyogenes to β-lactam antibiotics associated with mutations in the gene is geographically widespread [published online January 29, 2020]. J Clin Microbiol. doi:10.1128/JCM.01993-19