Global Genomic Analysis of Antimicrobial Resistance in Streptococcus pyogenes

Streptococcus pyogenes (Group A Streptococcus, GAS) is a major global pathogen. While macrolide resistance has been studied, large-scale analyses of overall antimicrobial resistance (AMR) in GAS across geographic datasets remain limited. This study aimed to comprehensively investigate AMR in GAS over more than a century.

A total of 47,689 high-quality S. pyogenes genomes from 59 countries, collected between 1900 and 2025 (predominantly post-1990), underwent quality control. Multilocus sequence typing and in silico prediction of AMR determinants using AMRFinderPlus v4.2.5 were performed. Temporal trends were analyzed via quasibinomial regression. Phenotypic susceptibility data from 310 isolates were interpreted using CLSI 2023 breakpoints.

GAS showed high genomic conservation (mean genome size, ∼1.81 Mb; ∼1,705 coding sequences). The non-macrolide resistome was dominated by tetracycline and aminoglycoside-associated genes, with tet(M) being the most prevalent (20.96%), followed by aph(3')-IIIa (8.50%), sat4 (8.30%), and ant(6)-Ia (7.69%). Overtime, the prevalence of sat4, aph(3')-IIIa, ant(6)-Ia, and tet(M) increased significantly, whereas that of tet(L), tet(O), and pbp2x_P601L declined (P < 0.05). Reduced susceptibility to selected β-lactams (cefuroxime, imipenem, meropenem) was sporadic (3-10%), primarily linked to pbp2x_P601L, whereas penicillin retained near-universal activity (99.7% susceptibility). Typical β-lactamase genes were rare and geographically restricted. Phenotypic resistance was detected for tetracycline (6%) and trimethoprim-sulfamethoxazole (4%), with 13% showing intermediate susceptibility to trimethoprim-sulfamethoxazole.

S. pyogenes remains highly susceptible to penicillin and other β-lactams. Resistance is mainly associated with tetracycline and aminoglycoside genes, which show dynamic changes over time due to ongoing selection pressures.