New Antibiotics, Biofilm Inhibitors, Vitamin Deficiency

I was not expecting my recent reading of an article on femtosecond reaction kinetics to produce another discussion of quorum sensing, biofilms and vitamins. The idea behind the article was to identify new targets for drug design based on the ephemeral transition states that occur as enzymes bind substrates, stabilize transition states and yield product molecules. Drugs that mimic the transition states make good enzyme inhibitors. One of the target enzymes for the control of disease is an enzyme, MTAN, involved in the synthesis of quorum sensing molecules that orchestrate the construction of common biofilms. The idea is to inhibit MTAN and also avoid selection for antibiotic resistance. Unfortunately, targeting quorum sensing molecules also may produce vitamin deficiencies, since many of these molecules, in this case vitamin K, are also quorum sensing molecules.

Drugs have too many Side Effects
Specificity in the binding of molecules to the thousands of proteins that are coded by the ca. 20,000 human genes depends on a very tight fit between the molecular "key" and the binding site "lock" of the protein. Just as in physical world, a small key/drug molecule with limited surface detail is not as safe/specific as a larger key with many surface features, and a larger lock/enzyme active site that is harder to pick/has fewer interactions with random enzymes. Unfortunately, most drugs are small molecules with limited surface features that make them like molecular skeleton keys that produce many side effects by interacting with unintended proteins/enzymes.

Transition States are more Specific
A recent focus on drug research is to exploit molecular computation and modeling to design molecules that will bind to the part of an enzyme that actually participates in binding substrates and catalyzing chemical reactions. These designed molecules can interact with an expanded region of the enzyme and bind more strongly than the normal substrate. The designed molecules can be very effective inhibitors that will not react as nonspecifically as inhibitors identified by trial an error, e.g. statins.

Biofilm Inhibitors are Targets for Antibiotic Development
The enzymes involved in the synthetic pathways of biofilm quorum sensing signals have been identified and powerful inhibitors of some of these enzymes have now been designed and synthesized. These inhibitors are very effective in inhibiting biofilm formation by some common bacterial pathogens (and essential gut flora.)

Biofilm Inhibitors will also Block Vitamin Production in Gut Biofilms
The new biofilm inhibitor antibiotics may have enhanced specificity, but they target enzymes that also provide essential functions in biofilms that are needed for healthy gut and immune system function. Many of the vitamins that are produced by gut flora are also quorum sensing signal molecules in healthy gut biofilms. Thus, blocking MTAN to block biofilm formation of a pathogen, will also block gut synthesis of vitamin K, which is made in gut bacteria using the MTAN pathway. These inhibitors would be expected to be particularly damaging to the specialized gut flora of breastfed babies, since these gut bacteria are known producers of vitamin K.

Statins and Atherosclerosis

A recent study (JUPITER) on the statin Crestor was ended prematurely when the drug was shown to dramatically reduce vascular events. The statin was tested on patients with chronic inflammation as judged by elevated C-reactive protein, but with low LDL. These patients would not normally be treated with statins and therefore represent an immense new market for statins.

Statins are supposed to act by interfering with the synthesis of cholesterol and thereby lowering the serum concentration of the lipid carrier LDL. Lowered LDL is supposed to decrease vascular disease that is aggravated by accumulation of cholesterol at sites of inflammation on the surface of blood vessels.

Unfortunately the data linking cholesterol production, LDL levels and vascular disease is weak. Thus, it is possible to lower LDL and have no impact on cardiovacular disease statistics. The recent study on Crestor was interpreted as being support for the link between LDL levels and vascular disease, but I think it shows something very different.

There is increasing evidence that vascular disease is based on diet-based chronic inflammation and that statins have a mild impact on reducing inflammation. It follows then that statins will reduce inflammation enough to have an impact on vascular disease, independent of effects on LDL levels. The Crestor study actually showed that patients with low levels of LDL but chronic inflammation benefited from lowering of inflammation. The LDL levels were unimportant. Reducing inflammation was the point and using statins to reduce inflammation is unnecessarily expensive and ineffective. Adjusting diet makes a lot more sense.

Drug companies are already pushing for increased use of statins on larger segments of the US population to provide prevention from atherosclerosis, stroke and heart disease. This would be immensely expensive with marginal returns. It is also just treating the symptoms without addressing the cause.

The solution to cardiovascular disease is dietary. Omega-6 oils and low availability of omega-3 fish oils is the major cause of the chronic inflammation that is the major risk factor for cardiovascular disease. The major US vegetable oils, corn, soybean, cottonseed, safflower, need to be drastically restricted and olive oil needs to be encouraged. We need to recognize that saturated fats are safer than the omega-6 polyunsaturated fats that have replaced them. Elimination of omega-6 vegetable oils and use of fish oil supplements are cheap and effective ways of lowering chronic inflammation.

Cardiovascular disease is also based on decreasing muscle mass, sarcopenia, which is also the basis for increasing chronic inflammation inappropriately attributed to aging. People get less physical exercise as couch potatoes or with decreasing activity as they age. The result is replacement of muscle by fat, and fat is inflammatory. Obesity is an extreme of this trend that leads to high chronic inflammation identified as metabolic syndrome, the prelude to a suite of nasty degenerative diseases: diabetes, atherosclerosis, allergies, cancer, Alzheimer’s, etc.

The obvious bottom line is to avoid all of these problems with an anti-inflammatory diet and lifestyle.