St. Jude Children’s Research Hospital discovery lays the groundwork for a new class of antibiotics to fight multi-drug resistant Staphylococcus aureus and related bacteria that cause serious infections.
St. Jude Children’s Research Hospital scientists have discovered an enzyme that regulates production of the toxins that contribute to potentially life-threatening Staphylococcus aureus infections. The study recently appeared in the scientific journal the Proceedings of the National Academy of Sciences (PNAS).
Researchers also showed that the same enzyme allows Staphylococcus aureus to use fatty acids acquired from the infected individual to make the membrane that bacteria need to grow and flourish. The results provide a promising focus for efforts to develop a much-needed new class of antibiotics to combat staph and other Gram-positive infections. Staphylococcus aureus is the most common cause of staph infections, including methicillin-resistant Staphylococcus aureus (MRSA), the drug-resistant infection that is a growing problem in hospitals.
“Staphylococcus aureus is a clear and present danger to patients worldwide,” said corresponding author Charles Rock, Ph.D., a member of the St. Jude Department of Infectious Diseases. “We set out to answer a long-standing question about bacterial membrane biochemistry and discovered a master regulator of the virulence factors that make staph infections so destructive and dangerous. The pathway we identified offers an exciting new target for antibiotic drug development.”
Virulence factors include dozens of proteins that bacteria make and secrete. The factors cause many symptoms and infection-related problems, including destruction of cells and tissue, and evasion of the immune system.
The enzyme Rock and his colleagues discovered is fatty acid kinase (FAK). Researchers showed that FAK is formed by the proteins FakA and FakB1 or FakB2. Scientists demonstrated how FakA and FakB work together to replace fatty acids in the bacterial membrane with fatty acids from the person infected.
Fatty acids are a key component of the phospholipids that make up a significant part of the bacterial membrane. Bacteria produce their own fatty acids, but some, including Staphylococcus aureus, can also borrow from their host, which reduces the demands on bacteria to make their own. Until now, however, the enzyme used to incorporate host fatty acids was unknown.
Researchers showed that different genes carry instructions for making the FAK proteins. Loss of the genes disrupted the ability of bacteria to incorporate host fatty acids into the bacterial membrane. “The big surprise was that loss of these genes also impacted production of virulence factors,” Rock said. “The mutant Staphylococcus aureus did not make the proteins responsible for many of the symptoms caused by these infections."
Earlier research from Rock hinted at a connection between fatty acid synthesis and production of virulence factors, but this study is the first to establish the biochemical link and identify the mechanism involved. Evidence suggests that FAK functions in the transcriptional regulation of virulence factor production, switching on genes that carry instructions for making the proteins. “In fact, FAK’s primary role in bacteria might be as a transcriptional regulator,” Rock said.
Researchers also detailed how FAK handles its duties related to membrane phospholipids. FakA includes the kinase domain, which allows the protein to function as an enzyme. FakB1 binds saturated fatty acids while FakB2 prefers unsaturated fatty acids.
When FakA interacts with either FakB1 or FakB2 a phosphate is transferred onto the FakB fatty acid, producing acyl-phosphate, a chemical intermediate not found in humans. The acyl-phosphate is used as a substitute for fatty acids normally made by the bacteria.
The paper’s first author is Josh Parsons, Ph.D., a postdoctoral fellow in Rock’s laboratory. The other authors are Tyler Broussard, Jason Rosch, Pamela Jackson and Chitra Subramanian, all of St. Jude; and Jeffrey Bose, of the University of Kansas, Kansas City.
The study was supported in part by a grant (GM034496) from the National Institutes of Health (NIH), a grant (CA21765) from the National Cancer Institute at the NIH and ALSAC.
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