Group A Streptococcus associated with recurrent tonsillitis form antibiotic-resistant intracellular communities

Group A Streptococcus (GAS) has remained universally susceptible to penicillin since the introduction of this antibiotic to treat GAS throat infections (“Strep throat”) in 1940’s. Despite this, a proportion of Strep throat infections fail to completely resolve with penicillin therapy, with recurrent infections requiring follow-up treatment with alternative broad-spectrum antibiotics. Here we show that GAS strains isolated from amoxicillin treatment failures are able to invade into epithelial cells and replicate in the presence of penicillin, forming large intracellular bacterial communities comprised of individual cells that are- and are not producing peptidoglycan. We further show that this process requires a GAS surface protein, Streptococcal fibronectin binding protein 1 (PrtF1), which promotes uptake into epithelial cells via a dedicated invasion pathway that leads to the penicillin-resistant phenotype. Our study describes a mechanism for phenotypic antibiotic resistance conferred by a bacterial invasin, and explains why penicillin often fails to clear GAS infections despite this pathogen being highly-susceptible to penicillin in vitro . Our findings may allow identification of GAS infections at risk of failing penicillin therapy at the point of care, and in turn allow treatment with alternative antibiotics to reduce rates of recurrent GAS infections.