Staph And Cholesterol: An Odd Couple
Cholesterol and MRSAs vie for headlines. Both are formidable topics of enormous interest to readers of mass media and to scientists (many of whom read mass media, probably in the bathroom). It turns out that Staphylococcus aureus and arteriosclerosis have something in common, although not in the way you might think. It happens that the yellowish-golden pigment of S. aureus is made by a pathway that, in its early steps, resembles the one for making steroids.
Let’s back up a moment. The S. aureus pigment is a carotenoid called staphyloxanthin. Although the discoverer of the organism, the Scottish surgeon Alexander Ogston, coined its species name in 1880, the role of the pigment has only been recently uncovered. It is essential for the virulence of the organism, acting as an antioxidant that detoxifies host-produced reactive oxygen species, such as O2–, ·OH, and HOCl. Mutants lacking the pigment are much less virulent. Sounds like blocking the synthesis of staphyloxanthin would be a good way to combat staph infections, no?
The pathways for making staphyloxanthin and steroids. Source
The early steps in the biosynthesis of staphyloxanthin and cholesterol are the same, up to the synthesis of an aliphatic precursor, presqualene diphosphate. Thereafter, the two pathways diverge. The next step is catalyzed by two different enzymes (the dehydrosqualene synthase CrtM for staph, the squalene synthase SQS for humans) that were shown in a recent paper to be structurally very similar. The authors asked if known SQS inhibitors might also inhibit the staph's CrtM and thus block staphyloxanthin synthesis. Sure enough, some did. Not only that, treating the staph with some of these compounds rendered them not only colorless but also less able to defend themselves from oxidant-based attacks by human leukocytes. Peritoneally infected mice survived better if given one of these new drugs. This is a neat new strategy. These inhibitor's are not antibiotics per se but anti-virulence factors. The organisms can grow perfectly well when cultured in their presence. But by blocking staphyloxanthin synthesis, these inhibitors render the staph defenseless against the reactive oxygen species produced by our immune system.
These compounds differ from statins, which work further downstream in cholesterol biosynthesis (and which would not be expected to affect the biosynthesis of staphyloxanthin). However, the inhibitors used here may also be medically useful for lowering cholesterol levels, a point that is under investigation. It is conceivable that some day one and the same drug could lower one’s cholesterol and prevent infections by S. aureus. But even without going that way, this work bodes well for the discovery of potent anti-staph drugs. Look out, MRSA!