Development of new antimicrobial agents and improved public health conditions have not substantially reduced the frequency of infections caused by Staphylococcus aureus. Staphylococci are the leading cause of osteomyelitis, septic arthritis, endocarditis, wound and foreign body infections. What constitutes the challenge in the treatment of staphylococcal infections is that staphylococci may resist treatment with conventional antimicrobial agents because of difficulties in achieving and maintaining therapeutically active concentrations of antibiotics in tissues which are either poorly vascularized (like bone) or harbor colonies of bacteria where diffusion is impaired (such as biofilms on surgical implants). Paradoxically, advances in the field of medical therapy have contributed to a steady increase of in the number of infections caused by coagulase-positive and -negative staphylococci by creating more situations in which these opportunistic pathogens find a suitable environment to multiply.
First described by Ogston more than a century ago, S. aureus has remained a mysterious pathogen. It is obvious that its virulence is multifactorial, and related to the production of a wide variety of extracellular and cell surface bound pathogenicity factors. The relative importance of these factors may vary depending on the site and stage of an infection, and various models have been proposed to explain the roles of individual factors. The most effective way to prevent an infection is early in the process of infection, before bacteria manage to multiply.
The concept of preventing infection by interfering with the initial microbial adherence to the host tissue is in this context particularly appealing. The molecular mechanisms of microbial adherence have been extensively studied for many Gram-negative bacteria, and only in the last decade shed some light on possible adhesion mechanisms of Gram-positive bacteria. Historically speaking, the association of S. aureus with fibrinogen (mediated by what was subsequently termed clumping factor, or less correctly, bound coagulase) described by Much in 1908 appears to be the first description of a putative adherence mechanism.
When Kuusela described binding of S. aureus cells to the then newly rediscovered fibronectin, a new chapter in the study of S. aureus adherence was opened (Kuusela, P., et al., Nature 276:718-720 (1978)). Soon, many other observations followed, indicating that 1) fibronectin may be recognized by many different bacteria, both Gram-positive and Gram-negative, and 2) in addition to fibronectin, many other connective tissue proteins are recognized and bound by bacteria. Currently the rate of description of new interactions between bacteria and connective tissue components, or eukaryotic cell surface components like integrins, seems to be limited only by the rate at which these components are discovered.
In addition to fibrinogen and fibronectin, S. aureus strains associate with several other adhesive eukaryotic proteins (many of which belong to the family of adhesive matrix proteins)--laminin (Lopes et al., Science 229:275-277 (1985)), vitronectin (Chhatwal, G. S., et al, Infect Immun. 55:1878-1883 (1987)), bone sialoprotein (Ryden, C., et al., Eur. J. Biochem. 184:331-336 (1989)), proteoglycans (Ryden et al., 1989), endothelial cell membrane protein (Tompkins, D.C., et al., J. Clin. Invest. 85:1323-1327 (1990)) and collagens. These interactions have mostly been studied in systems in which either soluble host proteins or microparticles coated with these proteins are incubated with bacteria. Indications that these bacteria-protein interactions play a role in virulence have been demonstrated in only few instances. Progress in this field has been relatively slow and may require a detailed knowledge of the bacterial components that serve as receptors for the matrix proteins.
As reported in the Apr. 15, 1994 edition of Science, for several years now, medical microbiologists have been tracking an alarming trend in microbial infection. It has been found that antibiotics that once killed bacterial pathogens with ease are becoming ineffective. This is the result of the remarkable ability of bacteria eventually to develop resistance to virtually every antibiotic medical research has utilized against them. Particularly worrisome is the relative dearth of new antibiotics on the horizon. And of the new antibiotics proposed, few employ novel modes of action that would be more difficult for bacteria to circumvent. Researchers and manufacturers have assumed that they have solved the problem of bacterial infection--after all, the market consists of over 100 antibiotics--and many pharmaceutical firms and research organizations have abandoned work on antibiotics or refused to fund these projects.
There are today strains of Staphylococcus which often cause fatal hospital infections that are immune to all but one existing antibiotic. It is predicted that it will not be long before that final barrier will fall.