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taphylococcus aureus is an ubiquitous human pathogen. Approximately 30% of healthy
individuals are colonized by S. aureus&emdash;typically in the nasal passages, in the vagina, or in the perianal area. In the United States, S. aureus is the major cause of nosocomial (acquired in a hospital) infections resulting in over 700,000 infections annually. Staphylococci can produce a variety of diseases ranging from food poisoning to toxic shock syndrome and sepsis.
The advent of antibiotics in the early part of this century was a pivotal development
in the treatment of infectious diseases caused by gram positive bacteria such
as S. aureus. Before antibiotics, mortality from gram positive sepsis
was in excess of 80%. The use of penicillin during World War II saved many lives
by curing sepsis due to the infections of wounds. However, in 1942,
penicillin-resistant strains of S. aureus were already being reported.
In the 1950's several serious outbreaks of staphylococcal infections by
penicillin-resistant strains had been reported. By 1997 resistance to penicillin
has risen to over 90% of isolates of S. aureus. A new B-lactam antibiotic, methicillin, came into clinical use in 1960. One year later, methicillin-resistant isolates were reported. Today, methicillin-resistant S. aureus (MRSA) are found in nearly 40% of clinical isolates. The aminoglycoside antimicrobial agent vancomycin is frequently the only drug available to the clinician for treatment of severe infections caused by MRSA strains. In 1997, the first clinical isolates of vancomycin-resistant S. aureus were reported. The specter of infections from multiply-resistant strains of gram positive organisms looms menacingly over the future human health. Recognition of this problem has led to the establishment of a network of international monitoring.
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| Path of peptide backbones of toxic shock syndrome toxin-1 (TSST-1) and exfoliative toxin A (ETA).
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In order to develop novel strategies for preventing and treating infections by S. aureus, workers in the laboratory of Supercomputing Institute Fellow Professor Douglas Ohlendorf are determining and analyzing the structures of a number of proteins produced by S. aureus that have been identified as virulence factors. Included among these proteins are a variety of toxins, proteases, lipases, and nuclease. By determining the structure of these molecules, it is possible to locate features required for biological activities. Mutation of these areas can produce molecules which can potentially be used as immunizing agents. For those enzyme virulence factors, the structure can be used to design inhibitors which block the action of these molecules. This approach, for example, has allowed the production of protease inhibitors recently coming into use in the treatment of AIDS.
Workers in Professor Ohlendorf's laboratory have been initially focusing on
two toxins that have activity as superantigens. The definition of a superantigen
is that it functions by binding to the foreign antigen-presenting molecule
(class II major histocompatibility complex) and to a specific serotype of receptor
on circulating killer T cells. In an infection produced by a superantigen, there
is a profound proliferation and then death of the T cells carrying the serotypical
marker on their surface. Professor Ohlendorf's group has determined the structures of toxic shock syndrome toxin-1 (TSST-1) and of exfoliative toxins A and B (ETA and ETB; see figure). TSST-1 is the key causative agent of the severe multisystem disorder toxic shock syndrome that gained notoriety in the 1970's with its association with usage of superabsorbant tampons. ETA and ETB are key agents in staphylococcal scalded skin syndrome&emdash;a typically nonfatal condition in children in which large areas of the skin blister and peel.
TSST-1 folds into a kidney-shaped 2 domain structure&emdash;one having five
B strands in a barrel and the other have a long a helix lying
against a sheet of four B strands. This fold has been also seen in the
B barrel; the axes of the two barrels are roughly perpendicular to each other. This fold is well known as that of the serine proteases. In fact, the ETs have a traditional active site, which if mutated, blocks the exfoliative activities while maintaining their superantigenic properties. The mystery is how molecules with different folds function as superantigens. This question is being studied computationally by calculating the congruence of molecular surfaces, and it has implications for protein design and genomics. Once similar surfaces have been identified, mutants can be made, expressed, and analyzed.
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