Moselio Schaechter


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April 28, 2008

Staph And Cholesterol: An Odd Couple

by Elio

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?

Final_figure

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!

Comments

I have colonized staph aureus folliculitis which usually shows up during stress. I also have a high total cholesterol 215- LDL-125. My triglyceride is 60,HDL is 70. I eat a low carb diet, and have lost 45lbs.my CRP is also elevated-3.0, and ESR is high-40. Could the staph be making the LDL,ESR and CRP high since its trying to fight the staph?

Statins exert their action by inhibiting HMG CoA reductase that leads ultimately to an upregulation of LDL receptors. Statins inhibit thise rate limiting "committed" step in cholesterol synthesis. Upregulated LDL receptors will then more efficiently clear LDL cholesterol from the blood as it circulates through the liver. Inhibition of squalene synthesis may not have any effect on cholesterol synthesis or LDL receptor levels since there may be probably alternative pathways once mevalonic acid is produced. To my knowledge, squalene production inhibitors have been tried for cholesterol reduction with poor results.

Hi,

Love your site very informational. I have high cholesterol and work very hard at controlling it. I exercise and try to eat a good diet low in fats. Your information will help me even more. I try to learn as much as I can about cholesterol. Thanks and keep up the good work!!!!!!!!!!!!!

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