Metabolites Turn On Pathogen's Virulence

Bacteria are known to use modular multienzyme systems—the polyketide and nonribosomal peptide synthesis (NRPS) machinery—to make complex biomolecules, most of which are antibiotics against microbial competitors. A new report by a Canadian group reveals that pathogenic Staphylococcus aureus bacteria use NRPS-synthesized molecules called aureusimines to attack humans (Science, DOI: 10.1126/science.​1188888). Finding chemicals that block aureus­imine production could lead to new antibiotics against this widespread Staphylococcus pathogen, which causes food poisoning, toxic shock syndrome, and other infections.

The team of researchers, led by Nathan A. Magarvey, a chemical biologist at McMaster University, in Ontario, has found that S. aureus makes the aureusimines itself. Those molecules activate a whole host of virulence genes encoding proteins that “do all sorts of nasty things to humans,” Magarvey says. In particular, these proteins lyse human blood cells as well as help the bacteria evade the body’s immune system and set up colonies in hosts. “The aureusimines are really dialed into staph’s ability to act as a pathogen,” Magarvey adds.

This “great paper” shows that “inhibition of aureus­imine biosynthesis may represent a completely novel approach to target this important human pathogen,” comments chemist Bradley Moore, who studies bacterial natural products at Skaggs School of Pharmacy, in San Diego.

The work also “adds a new layer of function for an NRPS secondary metabolite—to act as a master regulator for such a large number of virulence genes,” notes Mohamed A. Marahiel, a chemist at Philipps University, in Marburg, Germany, who has solved the crystal structures of several components of the NRPS machinery. NRPS metabolites are most often used as antibiotics; other roles in regulation have been observed much less often.

Magarvey is now looking for molecules that might block production of the aureusimines as possible new drugs against S. aureus. Compared with a drug that kills the microbe outright, one that knocks out only virulence might present less evolutionary pressure for S. aureus to develop resistance, he says.

“Penicillin was the first antibiotic against staph, and it is also an NRPS-produced peptide” from fungi, Magarvey says. Little did scientists know that “staph itself was using NRPS machinery for its own pathogenic purposes,” he adds.

Chemical & Engineering News

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