Antibiotic resistance and pathogenesis of Streptococci with focus on Group A Streptococci

Sammanfattning: Multi-drug resistant (MDR) infections remain the leading cause of death worldwide. MDR infections caused by Streptococcus pneumoniae (Spn), Streptococcus pyogenes (GAS) and Streptococcus agalactiae (GBS) are considered global threats to human health due to increased spread of antibiotic resistance and limited treatment options. In this thesis, we present the human milk derived HAMLET (Human Alpha-lactalbumin Made Lethal to Tumor cells) complex as a potential therapeutic alternative against streptococcal infections for its bactericidal and bacteriostatic activity against broth grown streptococci (Spn, GAS, or GBS). Adding to it, HAMLET potentiated antibiotic activity that renders antibiotic-resistant streptococci sensitive to the drugs they are resistant to, regardless of expressed serotype or antibiotic-resistance mechanism (target modification or efflux pumps). Biofilm formation and intracellular residence are antimicrobial avoidance mechanisms that help GAS escape host- or antibiotic-killing mechanisms. After completed antibiotic treatment against pharyngitis, intracellular bacteria may re-emerge and cause recurrent infections, leading to treatment failure. This thesis aims to identify novel therapeutic targets during respiratory infections by investigating GAS mediated pathogenic mechanisms. As most biofilms were studied on non-representative abiotic surfaces, we used a well-established biofilm model mimicking the respiratory niche to show that biofilm formation on pre-fixed epithelial cells is common in GAS. Proteome analysis of biofilm bacteria helped us identify proteins involved during biofilm formation and show that highly down-regulated protein expression is needed to form highly functional biofilms. In a live cell infection model, we show that biofilm bacteria internalize and persist equally long among GAS strains within epithelial cells. Using these models along with GAS strains lacking or expressing known virulence factors, we identify the role of these factors during biofilm formation and uptake into respiratory epithelial cells by GAS.Overall, the results obtained here are of clinical importance and could help in finding potential therapeutic strategies targeting streptococci during respiratory infections.