Common Medicines Make Superbugs, Not Prescription Antibiotics

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Careless prescriptions and cattle fattening antibiotics are blamed for the rise of superbugs resistant to everything in the hospital arsenal, but that’s all wrong.  Antibiotics fail, because we are all abusing common medicines that also have powerful antibiotic activity.  All painkillers, anti-inflammatories, statins, antidepressants, and the whole list of common pharmaceuticals are the problem.  We simply use too many drugs.

Common drugs should also be labeled as antibiotics, because they kill the sensitive bacteria in your gut and leave behind just the resistant bacteria.  Unfortunately, the genetic mutations that make your gut bacteria resistant to drugs, also provide resistance to antibiotics needed to stop infections and that broad resistance to antibiotics can spread to pathogens that then become the dreaded superbugs.

Here are the simple facts that I have discussed at length in another post:

• Statins were antibiotics that were repurposed to lower LDL, “bad cholesterol.”

• Aspirin was an antibiotic that was shown to relieve pain and inflammation.

• Metformin was an antibiotic that later proved useful for treatment of diabetes.

• Many chemotherapy drugs are antibiotics developed for cancer treatment.

• Diuretics were antibiotics that indirectly reduce blood pressure.

• Antidepressants, such as Prozac, Zoloft, etc. are antibiotics.

Common Drugs Are Actually Antibiotics

Most pharmaceuticals are derived from phytochemicals, a.k.a antioxidants, adapted in plants to kill microorganisms, i.e. as natural antibiotics.  It is not surprising that drugs = antibiotics.  What is surprising is that people assume that if antibiotics are labeled with some other activity, that they cease to be antibiotics.  All drugs are also antibiotics and that is why a major side effect of most medicines is upset gut bacteria.

Overuse of Common Drugs Produces Superbugs

Simply put, common medicines you swallow, kill bacteria in your bowels.  Some bacteria survive and are called “drug resistant.”  Bacteria accumulate resistances to several different kinds of drugs and are called “multidrug resistant.”  As might be expected, hospitals are the breeding grounds for multidrug resistant, mutant bacteria of all different types.  Unfortunately, anyone who takes several types of medications is also a source for multidrug resistant bacteria, so nursing homes are the most frequent sources of superbugs that cause outbreaks of hospital infections.

The Only Way to Stop Superbugs is to Use Less Drugs

The bottom line is that even if doctors start to use antibiotics more rationally and antibiotic use in agriculture is eliminated, superbugs will still be a big problem, because they will be produced by excessive use of common drugs, i.e. those found on the shelves of drug stores and supermarkets, as well as prescribed by doctors.  

The only solution to the superbug problem is to reduce pharmaceutical use by 99%.

Metformin, Antibiotic with Autoimmune Side Effects

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Metformin

Major points linked in this article:

• Metformin is commonly used in the treatment of diabetes.
• Metformin is structurally and chemically related to arginine, guanine and Canavanine.
• Side effects of Metformin include GI upset and autoimmune lupus (same with Canavanine.)
• Metformin also kills bacteria, i.e. it is an antibiotic.
• Many pharmaceuticals, e.g. statins, were first identified as antibiotics produced by fungi.
• Antibiotics select for antibiotic resistance genes, i.e. essential bacterial genes that have mutated to no longer be inactivated by antibiotics.
• New antibiotic resistance genes are combined with other resistance genes on multiple resistance plasmids that are transferred as a group.
• Because of its wide use, resistance to Metformin (and statins) as an antibiotic probably already exists and has been incorporated into multiple drug resistance plasmids.
• Many common pharmaceuticals are also antibiotics and probably select for multiple drug resistance.
• A major contributor to multiple drug resistance, “super bugs”, and the rapid loss of efficacy of antibiotics is the over use of pharmaceuticals in general, in addition to the specific abuse of antibiotics designed to kill pathogens.

Metformin is a Good Anti-Diabetic, but...

Arginine

Metformin is the treatment of choice for type 2 diabetes and yet, like many other common drugs, the full extent of its impact on the body (and the body’s essential microbiome of bacteria and fungi) has not been studied.  This article should not be seen as a criticism of the pharmacological efficacy of Metformin in lowering blood sugar.  The point here is that Metformin alters gut flora and its major pharmacological impact may result from alteration of the gut flora and not direct action on cells of body organs.  Metformin, because of its structure and size would be expected to act relatively indiscriminately in numerous cell functions, but I don't think that these interactions are as important as the impact on gut flora.  Metformin has all of the properties of an antibiotic selected to lower blood sugar and have limited side effects.  It would not be expected to cause a dramatic increase in autoimmunity, because diabetics already have elevated autoimmunity and associated deficiencies in gut flora.

Metformin is a Diguanide
 I previously explored the interesting properties of Metformin in my laboratory and through computer modeling experiments, and found it would react with many cellular enzymes and receptors similarly to the amino acid arginine.  This was no surprise, since the working end of arginine is a guanide and Metformin is a Siamese twin of guanides, i.e. a biguanide.  I might as well also say that another guanide, Canavanine, a toxic, antimicrobial phytoalexin in bean sprouts, has similar properties.

Canavanine

Phytochemicals as Antibiotics

  

I have studied (and written about) the natural plant antibiotics, phytoalexins, in legumes, and particularly in soy beans, so I would expect all of the chemicals, (a.k.a. phytochemicals or “antioxidants”) extracted from plants, e.g. alkaloids, polyphenols and essential oils, to kill bacteria and be toxic to human cells.  The selective advantage to plants in producing phytochemicals is the antibiotic activity of those chemicals.  Pathogens that have adapted for growth on one species of plant have resistance genes to that plant’s phytoalexins.  Thus, bacterial genes for resistance to the antibiotic activity of drugs derived from phytochemicals are common in nature and broad use of these drugs merely selects for the transfer of these genes to gut flora.

Canavanine and Lupus
What put together more pieces of the gut flora/antibiotic/autoimmune disease puzzle for me, was coming across Dr. Loren Cordain's recent reiteration of the toxicity of legumes and his singular example of Canavanine from alfalfa sprouts as a contributor to the autoimmune disease, lupus.  When I looked up the structure of Canavanine and found it to be a guanide, I immediately started making comparisons to Metformin and was amazed to see that these chemicals share the same list of side effects focused on the gut.  Moreover, lupus is also a side effect of both Metformin and Canavanine.  It was initially surprising, that a recent study suggests that the anti-diabetic action of Metformin may result indirectly from its antibiotic effects on gut flora.  I now expect that Canavanine causes lupus by killing or altering the metabolism of particular species of bacterial gut flora involved in the normal functions of the immune system, e.g. Tregs required for immune tolerance.  It is now a common observation that many pharmaceuticals act indirectly via their impact on gut flora, i.e. many pharmaceuticals are fundamentally antibiotics, and particular antibiotics can duplicate the activity of pharmaceuticals.

Pharmaceuticals Select for Multiple Antibiotic Resistance
I have one other concern about the wide use of drugs derived from phytoalexins.  Metformin can be considered one of those drugs, and just like phytoalexins, it is a potent antibiotic.  There is no difference between purified natural plant antibiotics/ phytoalexins/ polyphenols/ antioxidants and commercially synthesized antibiotics with respect to selecting for resistance.  I would expect that resistance to Metformin, as an antibiotic, has already developed in common gut flora and consequently, that multiple drug resistance plasmids from hospital pathogens now contain Metformin resistance.  Thus, I would also expect Metformin and many other pharmaceuticals to select for multiple antibiotic resistance. [An additional example is the antibiotic activity of NSAIDs on Helicobacter pylori.  I think that prevalent use of NSAIDs in many countries is responsible for the decline in H. pylori.]

SweetMyx Taste Enhancers, Alapyridains?

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I was just reading announcements of new synthetic chemicals (SweetMyx) to enhance the taste and help reduce sugar and salt in "health foods".  The new taste enhancers have already been approved by industry organizations that designate the chemicals as GRAS, generally recognized as safe.  I, of course, was curious about how the SweetMyx chemicals made food taste sweeter with less added sugar.  Notice how convenient it is that the food industry has found a way to charge more for less sugar, just as labels have been changed to specifically designate "sugar added:".

Alapyridains are Taste Enhancers

I searched the chemical literature for new taste enhancers, since the chemical ingredients in SweetMyx are trade secrets and will not be disclosed on food labels.  It didn't take long to find that the likely suspects are called alapyridains.  This group of related chemicals are synthesized with a central pyridine ring familiar from the related cytosine and thymidine of nucleic acids, the plant alkaloid nicotine and the vitamin niacin.  A guanide group (half of the diabetes drug metformin, which is a biguanide) is added to make a salt enhancer, and a benzene ring is added to make a sugar enhancer.  Without these additions, the central structure inhibits the ability to taste the bitterness associated with "healthy plant antioxidants," phytochemicals and essential oils.

Will SweetMyx Just Tickle your Taste Buds?

The alapyridains that I expect to be in SweetMyx seem to be similar to common plant alkaloids, which are natural pesticides and antibiotics, i.e. phytoalexins.  So I would expect these compounds to also be antibiotics with unknown impact on our gut flora, nervous and immune systems, just like all of the medical antibiotics.  Based on the general putative structure of the taste enhancers and similarity to other molecules with known reactivities I would also expect these molecules to react with enzymes that bind sugars, e.g. glycosidases, or with hundreds of other proteins that bind to heparin, e.g. embryological growth factors, clotting factors, cytokines, amyloids, etc., etc., etc.  It would also be expected that these enhancers will encourage consumption without satiety and therefore, just as artificial sweeteners, contribute to further obesity.  In other words, these taste enhancers can be expected to have numerous, unpredictable medical and ecological side effects that will not be understood for decades.

Aricept: dementia treatment

Aromatic Binding to Enzymes -- 

Aricept, an acetylcholine esterase inhibitor used to treat Alzheimer’s disease and other conditions that benefit from enhanced accumulation of acetylcholine, is an example of a molecule with multiple hydrophobic rings that binds to an enzyme.

I want to discuss aricept as an arbitrary example that I just looked up to illustrate the lack of specificity of statins that I will characterize in another article as little more than molecular skeleton keys that work on many different enzymes.

I have presented two diagrams of the structure of Aricept. It has two isolated rings on the left and then a fused pair of rings on the right. The major chemical feature here is the inability of the rings to hydrogen bond with water. The result is that water next to the faces of the rings is highly structured in a high energy configuration. Two rings will be at a much lower energy if they are stacked together, because two of the surfaces will no longer be exposed to water.

Typical low energy, noncovalent bonds in water, such as ionic bonds are readily broken by the thermal, kinetic energy of water -- they get knocked apart. The energy of these bonds is only 1-2 kcal/mol. In contrast, the stacked hydrophobic rings are quite stable, because it takes ten times the energy to separate them, 20 kcal/mol.

Aricept binds to acetylcholine esterase, the enzyme that degrades the neurotransmitter acetylcholine by at least three stacked rings. These ring structures are shown in the close up of the tunnel leading to the enzymes active site near the yellow tryptophan on the left. Part of the enzyme shown by the white, ribbon-like twists of the amino acid backbone have been removed over the tope of the grey-red and blue aricept molecule, to make it easier to see.

I also showed the aricept in the tunnel with the surface of the protein shown to indicate how the aricept slips and sticks in the enzyme and blocks its activity.

The aricept is bound to yellow tryptophans at both ends and the middle ring is bound to the hydrophobic ring of orange tyrosine. The geometry of the interaction is important, but many other molecules with fewer rings would also bind to the same hydrophobic, aromatic ring amino acids. Acetylcholine, which can form hydrogen bonds with the paired electons of the acetyl oxygens, will just slip across the surface of the hydrophobic rings on its way into the enzymatic tunnel.

Statins were found by testing fungal extracts for molecules that would inhibit an enzyme (HMG-CoA reductase) in lipid metabolism. The normal lipid substrates for that enzyme would also be expected to bind to the surface of rings in the acetylcholine esterase enzyme. In fact, I would expect to find molecules from fungal extracts that would inhibit acetylcholine esterase.

I demonstrated the nonspecificity of all of these binding events with the aromatic rings in the active sites of enzymes by having one of my students check for the binding of a flat hydrophobic molecule, metformin, one of the common drugs for treating type II diabetes, to a common bacterial enzyme, beta galactosidase. Kinetic studies demonstrated competitive inhibition of typical beta galactosidase substrates, which indicates that the metformin binds the aromatic amino acids that are known to be involved in binding of the sugar substrates, e.g. lactose, of the enzyme. I would not be surprised if the statins are transported into cells by the same organic cationic transporter that transports metformin.

I am setting the stage for a discussion in a future article of what kind of activities would be expected from fungal molecules that were identified by the statin screening. It is not surprising that the statins have many activities other than reducing LDL. The only statins that are effective in treating cardiovascular disease are those that also lower inflammation. It is also not surprising that statins have many side-effects.

There Is More Than Antioxidants

Every time a plant product has an impact on a disease it seems to be attributed to its antioxidant activity. Plant products are active, because they bind to proteins. They bind to lots of different proteins.

Krill oil is a good example. The anti-inflammatory activity of krill oil is due to its omega-3 oil (DHA and EPA) content, but krill oil is more potent than expected. Krill oil also contains a terpene, astaxanthene, that is probably derived from its algae diet. Astaxanthene is labeled as an anti-oxidant, but that is much too easy.

Astaxanthene consists of two flat, hydrophobic paddles, connected by a flexible, hydrophobic chain. Those paddles are important, because of their inability to hydrogen bond with water, i.e. hydrophobicity, and therefore their propensity to get stuck in contact with other hydrophobic surfaces. The list of candidate hydrophobic surfaces includes the obvious smaller aromatic rings (e.g. phenylalanine), indole double rings (e.g. tryptophan), and the less obvious sugars (e.g. galactose), unsaturated lipid/prostaglandins and basic amino acids (lysine and arginine). These are dominant cellular interactions.

The interchangeability of the hydrophobic paddle-binders means that astaxanthene can get its paddles stuck in enzyme or receptor protein active sites that normally bind a wide range of ligands (target small molecules, e.g. enzyme substrates). It is likely, therefore, that astaxanthene has anti-inflammatory activity, because it blocks an inflammatory interaction.

The ubiquity of interactions of terpenoids, based on their general structural properties, also gives these molecules access to cellular cytoplasm. These molecules are too large to diffuse through membranes and if they got half way through, they would be permanently stuck in the membrane. Terpenoids will tend to stick to carrier proteins that have hydrophobic patches or slots. These carriers will transport and internalize terpenoids and other similarly shaped molecules, e.g. steroid hormones.

Metformin, the diabetes drug, is another example of a molecule with a flat, hydrophobic side. It is a stretch to call this an antioxidant, but it is useful for this discussion, since one of my students tested to see it it would stick to a tryptophan in the active site of a classic enzyme, beta-galactosidase. Galactose, in the typical substrate for this enzyme, lactose, will bind to the active site, because of a prominent tryptophan. The shocker is that my student showed that metformin also binds to that same site and competes with lactose. Astaxanthene would also be expected to bind in the same way.

Curcumin is one of the most potent anti-inflammatory compounds and the main ingredient in turmuric, binds to proteins that inhibit the inflammatory transcription factor, NFkB. I would expect astaxanthene to also inhibit NFkB.

Capsaicin is a related molecule that binds to the heat/pain sensor in skin and blocks pain sensation. That is how capsaicin is used as a topical analgesic. Castor oil, ricinoleate, binds to the same sensor and competes with capsaicin and also is an effective pain reliever. Note that ricinoleate is a modified fatty acid that could curl up on the same hydrophobic paddle surface as capsaicin.

The bottom line of this discussion is that if someone tries to convince you that resveratrol, the anti-aging ingredient in wine, is an anti-oxidant, be skeptical. Expect that resveratrol will have numerous interactions with proteins and many of those will not be known.

Topoisomerase Inhibitors

Inhibiting enzymes involved in DNA synthesis should stop cancer cells, because cancer is uncontrolled cell division. Topoisomerases are enzymes that help to relieve the twists on double helical DNA as it unwinds preparatory to replication. It appears logical that topoisomerase inhibitors should be cancer inhibitors. Unfortunately targeting DNA-binding proteins also targets most of the signal receptors that are the targets for the evolution of plant alkaloids.

Drugs are designed to be specific in their interactions with a particular target protein, but they are too small to be specific and end up binding to many other related proteins. Hence, drugs have side reactions that are to some extent unpredictable, because the interacting proteins are not known.

Aspirin, for example, is supposed to bind to and inhibit COX-2, the enzyme that converts omega-3 and omega-6, long-chain fatty acids into corresponding anti-inflammatory and inflammatory prostaglandins, resp. Aspirin also binds to proteins that inhibit NFkB, the transcription factor that controls expression of inflammatory genes. Aspirin binds to dozens of other proteins. Aspirin does lots of other things than just blunt inflammation, but those side reactions are usually not significant enough to get our attention.

Heparin is one of the most commonly used drugs. It binds to and activates an inhibitor of thrombin, an enzyme that activates fibrin and mediates clotting. Heparin also binds to other components of the clotting system, as well as a dozen components of the complement system, and most of the cytokines that control communications throughout the body. When patients are given heparin injections, heparin binds continually to all of these components and must be constantly supplemented and monitored. Inflammation depletes the heparin components throughout the body, so it is not known prior to injection, how much heparin will be needed to saturate other serum proteins before the desired level of clotting inhibition is achieved. This illustrates rather dramatically that most drugs have only limited specificity.

One of my students provided another example of the minimal specificity of small molecules, especially the alkaloids and phenolics produced by plants. He brought to me a research article espousing the use of phenolics from yerba mate, which serves as a coffee-like stimulant in Argentina, as a topoisomerase inhibitor and potential anti-tumor treatment. Sure enough, phenolics extracted from this plant inhibit topoisomerase, and they may well be able to inhibit the growth of tumors, but it is doubtful that the binding of the phenolics to topoisomerase in the tumor nuclei has anything to do with inhibition of tumor growth.

Topoisomerase binds to nuclear DNA as the DNA unwinds during replication to produce two new double helical DNA molecules. Topoisomerase is a DNA-binding protein, i.e. a protein that binds to a negatively charged polymer of small deoxyribose sugars and flat purine and pyrimidine bases. Proteins bind to DNA in two ways. Amino acids of the protein either bind along the edges of the hydrophobic stack of base pairs, e.g. sequence-specific transcription factors, or they provide hydrophobic, flat surfaces that bind to the hydrophobic faces of the separated bases. Topoisomerase does both, because it deals with single-stranded regions of DNA and therefore binds to both the phosphates, as well as the bases. The important point here is that both aromatic amino acids, with flat hydrophobic rings, and the hydrophobic tails of basic amino acids, i.e. lysine and arginine, bind to the hydrophobic faces of nucleic acid bases.

I have illustrated the binding of a “topoisomerase inhibitor” to show the arginine (blue) in the active site cleft of the topoisomerase that binds across the hydrophobic face of the inhibitor (grey and red). Many plant phenolics and alkaloids would be expected to similarly bind and act as inhibitors of topoisomerase. This observation and the ease by which alkaloids enter cells (attached to circulating heparan sulfate?) suggests that a major function of the nuclear envelope may be to minimize access of alkaloid and related molecules to the nucleic acid binding proteins of the nucleus.

The binding promiscuity of secondary plant products is further exemplified by berberine. Berberine is an alkaloid found in goldenseal and is an herbal remedy used to treat a variety of inflammatory diseases. It also binds to heparin (and nucleic acids) to produce a fluorescent complex. Thus, mast cells that store and secrete histamine and heparin to produce the symptoms of allergy, can be vividly stained with berberine.

I could not resist the temptation to check to see if berberine also binds to topoisomerase. A quick search of the research literature showed that berberine is in fact a topoisomerase inhibitor.

The numerous cross reactions of drugs are further illustrated by metformin, the common drug used in the treatment of type II diabetes. Metformin is approximately planar and provides a surface that cannot hydrogen bond, i.e. it is hydrophobic. I expected that metformin would bind to tryptophans that I observed as common substrate-binding amino acids in the active sites of proteins that bound to polysaccharides, e.g. lectins, glycosidases and glycanases. To test this, I had students in one of my courses examine the inhibitory activity of metformin on E. coli beta-galactosidase. They found measurable inhibition and support for competitive binding to the active site that contains a pair of the predicted tryptophans.

My protein modeling and structural studies show the basis for numerous interactions between plant secondary compounds, drugs, nucleic acids, polysaccharides (glycosaminoglycans, e.g. heparin) and proteins. Unpredicted cross reactions abound and every drug can be expected to interact with multiple proteins. This provides a note of caution to the use of any drug and encourages minimal exposure, since many unobserved and unanticipated side effects are occurring. These observations also question routine ingestion of herbal remedies, after all, plants use their secondary products as potent defenses against being eaten. Alkaloids disrupt nervous systems and cellular signaling. Plants are not naturally safe.