Ann Clin Microbiol 2026;29(3):11. Molecular mechanisms, epidemiology, and clinical implications of macrolide resistance in group A Streptococcus: a narrative review
| Mechanism | Explanation | Clinical significance | Representative reference (first author, year) |
|---|---|---|---|
| Lack of alterations in PBPs | GAS rarely develops mutations in PBPs, the primary targets of β-lactam antibiotics, unlike Streptococcus pneumoniae | Prevents emergence of intrinsic β-lactam resistance | Musser, 2020 [32] |
| Absence of β-lactamase production | GAS does not produce β-lactamase enzymes capable of degrading penicillin | Ensures continued efficacy of penicillin therapy | Yu, 2023 [34] |
| Limited horizontal gene transfer | GAS has a relatively low capacity to acquire β-lactam resistance genes from other bacteria | Restricts dissemination of resistance determinants | Horn, 1998 [33] |
| Potential fitness constraints associated with some PBP alterations | The fitness effects appear mutation- and genetic-background-dependent, and reduced β-lactam susceptibility does not invariably impose a prohibitive fitness cost. | May limit persistence or dissemination of some variants, depending on mutation and genetic background | Musser, 2020 [32] |
| Lack of documented clinical resistance | No confirmed penicillin-resistant GAS strains have been widely established in clinical practice | Supports penicillin as first-line therapy | Musser, 2020 [32] |
| Treatment failures unrelated to true resistance | Failures are associated with intracellular persistence, biofilm formation, or poor adherence rather than resistance | Reinforces continued clinical reliability of penicillin | Brook, 2017 [35] |
Despite more than 80 years of clinical use, GAS remains predictably susceptible to penicillin according to current clinical susceptibility criteria; several biological and evolutionary mechanisms have been proposed to explain this sustained susceptibility.
Abbreviations: GAS, group A Streptococcus; PBP, penicillin-binding protein.