Berberine sulfate is an alkaloid extracted from the roots and bark of various plants and possesses antibacterial, antifungal, and antiprotozoal activities. Most studies have focused on the bacteriostatic or bactericidal activities of this compound. In this study, we report that berberine sulfate is bacteriostatic for streptococci and that sub-MICs of berberine blocked the adherence of streptococci to host cells, immobilized fibronectin, and hexadecane. Concentrations of berberine below its MIC caused an eightfold increase in release of lipoteichoic acid from the streptococci. Higher concentrations of berberine directly interfered with the adherence of streptococci to host cells either by preventing the complexing of lipoteichoic acid with fibronectin or by dissolution of such complexes once they were formed. Thus, berberine sulfate interferes with the adherence of group A streptococci by two distinct mechanisms: one by releasing the adhesin lipoteichoic acid from the streptococcal cell surface and another by directly preventing or dissolving lipoteichoic acid-fibronectin complexes.Berberine sulfate is an extract of plants that has been used either as a crude extract or in pure form to treat trachoma (19), diarrhea (9, 14, 18, 20), amoebiasis (12, 24), and pharyngeal pyogenic infections (25). The drug thus appears to have a broad antimicrobial activity (2) and seems to be relatively nontoxic to humans (9, 18), even though it and its derivatives intercalate themselves into DNA and phospholipid bilayers (5, 13) and inhibit enzymes such as alcohol dehydrogenase and xanthine oxidase (22). These latter activities probably account for the ability of berberine sulfate to inhibit reverse transcriptase activity and thereby to inhibit the replication of certain retroviruses (22).The efficacy of berberine sulfate in the treatment of certain bacterial diseases appears to be primarily dependent upon its direct antibacterial effects. In some cases, however, berberine appears to be efficacious even though high concentrations of the drug have no effect on bacterial growth. The therapeutic effect of berberine sulfate against enterotoxigenic Escherichia coli was suggested to be due to its antisecretory effects on the host rather than any effect on the invading organisms (18,20).In most studies of the anti-infectious activities of berberine sulfate, the focus has been on its antimicrobial effects; little or no attention has been paid to the effects of berberine on the adherence of bacteria to host cells. Since adherence of an organism to mucosal surfaces usually precedes invasion, some of the beneficial properties of berberine could be due to interference with the adherence process. The present study was undertaken to determine the effects of berberine sulfate on the adhesive properties of Streptococcus pyogenes. These microorganisms adhere to epithelial cells (3, 4), fibronectin (6, 23), and hexadecane (7, 17); in each case, lipoteichoic acid (LTA) has been found to be the major streptococcal surface molecule involved in adherence...