A nonpeptide integrin antagonist can inhibit epithelial cell ingestion of Streptococcus pyogenes by blocking formation of integrin alpha 5 beta 1-fibronectin-M1 protein complexes

Streptococcus pyogenes can be efficiently internalized by a variety of huma n epithelial cells, beta-lactam antibiotics, commonly used to treat S. pyog enes infections, do not readily permeate mammalian cells, There is growing evidence that the ability of streptococci to enter host cells contributes t o the frequent failure of antibiotics to eradicate the organism from infect ed individuals. Recent studies have suggested that host cell entry requires the formation of a complex of a bacterial fibronectin (Fn) binding protein (e.g., M1 protein or protein F1/Sfbl), human Fn, and the epithelial cell F n receptor, integrin alpha 5 beta 1. We report here that a low molecular we ight, nonpeptide antagonist of integrin alpha 5 beta 1, SJ755, can inhibit internalization of streptococci by primary human tonsillar epithelial cells and immortalized human epithelial (A549) cells, thus increasing the extent of bacterial killing by antibiotics. SJ755 blocked Fn binding by human ton sillar epithelial and A549 cells, suggesting that integrin alpha 5 beta 1 i s the major Fn receptor expressed by both cell types. SJ755 did not affect Fn binding by purified M1 protein or M1(+) bacteria. Purified M1 protein fa iled to associate with integrin alpha 5 beta 1 unless the integrin had been prebound by Fn. Also, SJ755 blocked formation of alpha 5 beta 1-Fn-M1 comp lexes in vitro. These results support the previous proposal that Fn functio ns as a molecular bridge between M1 protein and integrin alpha 5 beta 1. Fu rthermore, these results suggest that integrin antagonists may enhance the efficacy of antibiotics in treatment of S. pyogenes infections.