Prior studies suggest Staphylococcus aureus exotoxins are not produced when the organism is cultured in human blood. Human blood was fractionated into plasma and water-lysed red blood cells and demonstrated that mixtures of α and β globins of hemoglobin (as low as 1 ug/ml) inhibited S. aureus exotoxin production while increasing production of protein A and not affecting bacterial growth. Pepsin but not trypsin digestion destroyed the ability of α and β globin to inhibit exotoxin production. Exotoxin production by both methicillin-resistant and susceptible organisms was inhibited. Production of streptococcal pyrogenic exotoxin A by Streptococcus pyogenes was unaffected by α and β globin chains, but was inhibited when produced in S. aureus. Use of isogenic S. aureus strains suggested the targets of α and β globin chains, leading to inhibition of staphylococcal exotoxins, included the two component system SrrA-SrrB. Delta hemolysin production was also inhibited, suggesting the two component (and quorum sensing) system AgrA-AgrC was targeted. The α and β globin chains represent promising molecules to interfere with the pathogenesis of serious staphylococcal diseases.Staphylococcus aureus causes large numbers of human diseases, primarily initiated by colonization of mucosal surfaces (1,2). At any particular time, as many as 40% of humans may be colonized by culturable S. aureus strains on either nasal or vaginal mucosal surfaces (1,3). The organism may cause relatively benign infections, such as boils, and life threatening infections such as toxic shock syndrome (TSS) (4), scalded skin syndrome (5), necrotizing pneumonia (6-8), and the recently described staphylococcal purpura fulminans (9,10). Antibiotic resistance in S. aureus strains is an ever increasing problem, with recognition of both community-and hospital-associated methicillin-resistant strains (MRSA) (1,2,11). † This work was supported by a research grant from Procter & Gamble, Cincinnati, Ohio and USPHS research grant HL36611 from the National Heart, Lung, and Blood Institute.*To whom correspondence should be addressed. Phone: 612-624-1484; Fax: 612-626-0623; E mail: schli001@umn.edu Recently, two methicillin-resistant, vancomycin-resistant strains were isolated in association with human infections (12,13).The ability of S. aureus to cause serious human diseases depends on production of both cellsurface and secreted virulence factors by the organism (1,4). The cell-surface virulence factors, often referred to as microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) (14), allow the organism to attach to host tissues and in some instances evade the host immune system (15). MSCRAMMs include staphylococcal protein A. The secreted virulence factors, including a large array of exotoxins, allow the organism to gain access to nutrients and avoid the host immune system (4,5,16). For example, the hemolysin family of exotoxins allows the organism both to resist destruction by leukocytes and at the same time gain access to host tissue ...