Antibiotic Resistance, Superbugs and Drugs

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Antibiotic resistance results, because spontaneous mutations occur so frequently that all bacteria are different.  It is just a matter of exposing enough bacteria to an antibiotic to find one that is insensitive to a particular antibiotic.  More bacteria mean a greater chance of mutations to antibiotic resistance.  The gut contains a lot of bacteria and sewage treatment plants are loaded with gut flora.

Health in Diagrams

Antibiotics are Ubiquitous

All organisms, plants, fungi and animals/humans produce chemicals that kill bacteria, i.e. antibiotics.  I have written many articles about the natural antibiotics of plants, a.k.a. phytoalexins or “antioxidant” polyphenolics, and the human defensins that are peptides with heparin binding domains.  Bacteria also produce viruses, called bacteriophages, that kill other bacteria.  All of these natural antibiotics are small molecules that interact with many different human proteins, and it is these side effects that permit their exploitation as pharmaceuticals.  Thus, statins were selected from fungal antibiotics that inhibited an enzyme needed for human synthesis of cholesterol, metformin was a phytoalexin found to reduce blood sugar and resveratrol is a grape phytoalexin.

Plant Antibiotics are Natural

The flavoring chemicals in herbs and spices have a far more important use in food preparation than titillation of taste buds, since those chemicals kill common food pathogens.  More profoundly, it is important to realize that the selective advantage of phytochemicals/polyphenols/alkaloids/essential oils to the plants that make them, is as natural antibiotics.  Plants kill bacteria, as well as fungi and insects, for a living.

Plant Chemicals Attack all Aspects of Bacteria

Most of the thousand genes that are present in a bacterium code for proteins/enzymes and most antibiotics target those enzymes.  Penicillin binds to an enzyme needed to make bacterial cell walls, streptomycin target protein synthesis, rifampicin blocks RNA synthesis, actinomycin D inhibits DNA synthesis, etc.

Mutation to Antibiotic Resistance is Automatic in Bacteria

Each time a cell replicates, mistakes are made and the new DNA molecule of each chromosome is slightly different than the original.  There are about a thousand genes on the single chromosome of a bacterium and about the same number on each of the 23 human chromosomes.  About a dozen mistakes, mutations, are made each time bacteria replicate.  The mutations that alter the gene target of an antibiotic and produce a bacterial enzyme that is unaffected by the antibiotic, yield an antibiotic resistant bacterium.  The mutant gene now codes for antibiotic resistance and the presence of several resistance genes in the same bacterium produces multiple antibiotic resistant "superbugs."

Mutations are Random, but Antibiotics Select for Resistance

Each cellular replication produces random mutations throughout the bacterial DNA, but of the billion sites along the DNA that can mutate, only a few will produce a modified enzyme that will no longer interact with a particular antibiotic and thus be resistant.  Antibiotic resistance mutants are rare, less than one in a million, but a million bacteria can grow from a single cell in a day and occupy a volume less than a crystal of salt.  Ten hours later, after ten more doublings of the million bacteria, there will be a billion, and there will be a good chance that among those will be a mutant that is resistant to a particular antibiotic.  In the pound of bacteria in the human gut, there are mutants that are resistant to most antibiotics, including the antibiotics that have not yet been developed.  Of course, most of those antibiotic resistant bacteria are just flushed down the toilet.  Treatment with antibiotics kills all of the sensitive bacteria and leaves only the resistant.  Thus, antibiotic treatments select for antibiotic resistant bacteria.

Common Use of Antibiotics Selects for Resistance on Plasmids

Genes are transferred between bacteria by bacteriophages, conjugation (a kind of bacterial sex) and transformation, which is the release of DNA from one bacterium with subsequent uptake by another.  Biofilms, which are communities of many different species of bacteria, stimulate transformation and exploit bacterial DNA as a matrix material to hold the communities together.  The human gut is lined with biofilms and the biofilm bacteria secrete vitamins as the quorum sensing signals that coordinate community activity.  Thus, some vitamins must stimulate transformation, the exchange of DNA among members of the different species of bacteria in the biofilms with evolution of new and novel species.  Rapid change in the gut environment selects for a shift in genes that provide for adaptation to the new environment to small DNA fragments, plasmids, that move most readily between bacteria.  Antibiotic treatment results in antibiotic resistance genes on plasmids.

Use of Multiple Antibiotics Selects for Multiple Antibiotic Resistance Plasmids

Persistent use of an antibiotic will spread resistance to a particular antibiotic through the gut flora, facilitated by antibiotic resistant plasmids.  Replacement of a second antibiotic will result in a new plasmid with both antibiotic resistance genes.  Hospitalization and exposure to a plethora of bacteria with multiple antibiotic resistance plasmids will result in rapid conversion of gut flora to multiple antibiotic resistance upon exposure to any antibiotics.  Hospital staff would be expected to be natural repositories for multiple resistance genes, especially if they are exposed to any antibiotic (or pharmaceutical.)

Most Pharmaceuticals Select for Multiple Antibiotic Resistance Plasmids and Superbugs

The frightening rise of superbugs resistant to all known antibiotics has been attributed to the accelerated use of antibiotics in medicine and agriculture.  Mixing megatons of bacteria in the guts of billions of people with tons of antibiotics, and still more in sewage treatment plants and agriculture, is bound to produce bacteria with every type of multiple antibiotic resistance plasmid imaginable.  But that is not the biggest problem, since fingering the commercial use and misuse of antibiotics ignores biggest exposure of bacteria to antibiotics.  It ignores the fact that most popular pharmaceuticals, NSAIDs, statins, anti-depressants, anti-diabetics, etc., also have substantial antibiotic activity.  Most of these pharmaceuticals started out as phytoalexins and then were found to also have pharmaceutical activity.  Pharmaceuticals are just repurposed natural antibiotics.  When you take an aspirin or Metformin or a statin, you are taking an antibiotic.  When you take a pharmaceutical, you are selecting for multiple antibiotic resistance plasmids in your gut flora and you may be making the next superbug.

Phytochemicals, Natural Antibiotics and Antioxidants

Plants are mean and sneaky.  They are natural organic chemists and make the nastiest toxins on earth.  Never trust a plant.  Eat them at your peril… or because they taste good.

Phytoalexins

Plants are Fast and Lethal

I was shocked when people started to laud the virtues of phytochemicals.  I thought that they must have alkaloid poisoning.  My PhD training involved separating and measuring the antifungal chemicals produced by soybean cotyledons exposed to the wall polysaccharides of a pathogenic fungus.  The plants would go crazy and produce a witch’s brew of toxins to provide protection from the fungus.  I eventually wrote a chapter on these toxic natural antibiotics, phytoalexins, for the Encyclopedia of Science and Engineering.  All plants produce these chemicals and as one might expect, seeds/nuts are provided with special protection to avoid being digested.

Lignin

Plants are Natural Chemical Killers

I developed a profound respect for the ability of plants to protect themselves.  Fungal spores germinate on the surface of leaves and their slender, threadlike hyphae attach and glue themselves to the waxy outer surface and then forcefully and enzymatically penetrate to the spongy cells below.  When the tip of the hypha touches the wall of the underlying cell, the plant nucleus lurches as its cytoskeleton reorients.  The surrounding plant cells respond in sympathy and all of these neighbors mobilize their biochemical processes to kill everything in their vicinity.  In a few hours, the plant chemicals kill the cells producing them along with the pathogen, and would continue to kill more and more of the leaf, but plant cell walls also contain enzymes that convert the phytoalexins to more wall material, lignin, and protect cells outside of the influence of the fungus.  As lignin in wood and plant litter is slowly degraded by microorganisms, it forms humus, the natural organic material in compost and soil, and also releases a potpourri of potent plant phenolics like BPA.  Compost is also a rich source of cell wall polysaccharides, a.k.a. soluble fiber, that feeds soil bacteria.

Phytochemicals are Natural Antibiotics

Most phytochemicals have evolved in plants as pathogen or herbivore defenses.  Since the nervous system is adapted to detect other organisms, it is not surprising that plants target the sensory system, brain and nerves of herbivores, and we detect the flavor and smell of plants/herbs/spices by their defensive molecules.  All of the flavor and taste components of herbs and spices are phytochemicals that kill bacteria, fungi and other pathogens.  Nicotine and caffeine are insecticides.  A detailed, worldwide study showed that spices are used in specific global areas, because of the local availability of the spices and their effectiveness against local food storage pathogens.  People develop a taste for the plant defensive chemicals that they must be exposed to for sustenance.  Cuisine represents a knife edge that separates attractive stimulation from death.  Natural or organic does not mean safe or healthy.  Plants are as dangerous to eat as pufferfish.

Phytoalexins are Useful, but Be Very Careful

Perfume Ingredients

If a grape notices a nearby fungal pathogen, it produces its phytoalexins, including resveritrol, which is a notable “antioxidant” that has been recognized as contributing to longevity.  People are encouraged to drink red wine for the health benefits of its phytoalexins.  Most of the pharmaceuticals derived from plants are phytoalexins in disguise.  Of course, the evolutionary origins of phytoalexins as natural broad spectrum antibiotics, makes it no surprise that phytoalexins are commonly toxic, carcinogenic and very dangerous to fetuses.  Morning sickness has been explained as nature’s way of telling a mother carrying a vulnerable fetus to not eat plants and potentially phytoalexins.  It is wise for women to avoid plants, perfumes and essential oils during their first trimester.  Essential oils are phytoalexin extracts from plants and many of these components are the essence of perfumes.  These same chemicals, e.g. limonene, serve dual purposes as fragrances and paint strippers, recreational drugs and insecticides.  We can smell these natural plant chemicals, because they are attacking our nervous system.  Multipurpose mixtures of essential oils, such as Vick’s Vaporub, contain menthol, camphor, eucalyptus oil and terpentine that kill bacteria and fungi (toe nail fungus) and also stimulate cold/hot sensing nerves in the skin, which triggers endorphin production and reduces underlying joint inflammation.

Fruits are Fake Seduction

Fructose is fruit sugar.  That is very appropriate.  Fructose derivatives are the most central intermediates of central metabolism, glycolysis; glucose is immediately converted to fructose after it enters a cell as the fundamental source of energy and carbon building blocks.  Fructose is not normally transported in plants or animals, because it is too chemically reactive and toxic.  It rapidly bonds and crosslinks proteins and is ten times worse than glucose in forming AGE (advanced glycation end products) such as hemoglobin A1C.  If you feed fructose to cattle, it makes their meat tough by cross linking protein fibers and it does the same thing to human skin.  Fructose in fruit is a fake, because it is cheap and sweet.  Animals eat fruit hoping to find starch, which is the only polysaccharide that animals can convert to glucose with their own (not bacterial gut flora) enzymes.  Starch quickly becomes sweet, because amylase in saliva digests the long chains of glucose molecules of starch into shorter dextrins that trigger sweet sensors in the tongue.  Fructose masquerades as starch by binding to sweet sensors a hundred times more strongly than dextrins.  The evolutionary advantage to using fructose to make plants sweet is that it takes much less energy and carbon, and it also poisons insects and microorganisms.  That is why honey is made of equal amounts of fructose and glucose, rather than sucrose, for example.  Fructose in high concentrations is toxic to microorganisms and honey can be used to dress wounds.  I can’t understand why fruits, especially juices, are recommended as part of a nutritional diet.  At best, fruit should be converted into juice.  The juice should be discarded and the pulp eaten as a source of soluble fiber, pectin, to feed gut flora. 

Phytochemicals Must be Detoxified to be Edible

Bacterial and fungal pathogens must avoid detection by plants to avoid death by phytoalexins.  Insects, similarly must avoid preformed phytochemicals that would kill or poison them with their first bite.  Pathogens and pests that are effective on one species of plant cannot eat others with different chemical defenses; plants and their pests/pathogens are mutually adapted.  Primates browse on new shoots of many different types of plants, to avoid building up lethal doses of particular phytochemicals.  The same is true of humans, who also have intestines and livers that chemically treat and neutralize plant toxins.  These same human defenses determine the rate at which other related chemicals, i.e. pharmaceuticals, most of which are derived from phytoalexins, are transformed and excreted.  Turmeric contains curcumin, which is the most potent inhibitor of inflammation yet identified.  Unfortunately, curcumin is “detoxified” in the intestine and large amounts must be eaten to suppress inflammation.  Fortunately, pepper contains another phytoalexin, piperine, which inhibits the detox system, so that most cuisines that use turmeric combine it with black pepper.

Trade Your Liver for Vegetables

The liver is the only organ that can be continually regenerated and that is because humans have evolved to eat plants, and phytoalexins take their toll on the liver.  As plants are digested and absorbed in the small intestines and transported to the liver, phytoalexins accompany the nutrients.  Most of the phytochemicals are chemically detoxified by liver enzymes, but the phytoalexins kill some liver cells with each meal and some of the phytoalexins circulate in the blood and reach other tissues.  The phytoalexins are evolutionarily adapted to bind to proteins to disrupt essential enzymes of microorganisms and herbivores, and like pharmaceuticals to which they are chemically and functionally related, they have numerous side effects.  The chemical reactivity is what is detected as the “antioxidant” property of phytoalexins.  Antioxidant is nutritionally meaningless and basically reflects the chemical toxicity of phytochemicals.  After all, you can’t easily sell chemicals that are inherently toxic.  Meat and humans are made of the same easily digestible stuff, i.e. protein, fat, plus indigestible polysaccharides in connective tissue, i.e. chondroitin sulfate and heparan sulfate.  Plants are essentially anti-human and are made of protein, vegetable oils (omega-6), digestible starch, undigestible cell wall polysaccharides, undigestible lignin and toxic phytoalexins.  Humans have adapted to eating plants with liver enzymes, liver regeneration, gut flora (to eat otherwise indigestible polysaccharides, soluble fiber to produce short chain fatty acids) and elaborate cultural habits.  We avoid most plants as too toxic and have domesticated some to produce reduced and tolerable levels of phytochemicals.  Of course this also means that the domesticated, defanged crop plants have a hard time defending themselves and we have to continually worry about blights and pestilences, and end up applying our own witch’s brew of fungicides, pesticides, and herbicides.

Polyphenols and Hormesis
I am going to add a few comments on the benefits of phytochemical "antioxidants", a.k.a. polyphenols, to clarify what I think is a misuse of the term "hormesis", which I thought meant the dilution of a toxin until it reached a magic lower concentration which was beneficial.  The trade offs of phytochemicals are nicely discussed by the Whole Health Source blogger, Dr. Stephan Guyenet.  I just don't think that the benefit of toxic chemicals stimulating the body's own antioxidant arsenal is an example of hormesis.  The point is that phytochemicals always act as toxins and stimulate toxin defenses.  Phytochemicals don't act as anti-oxidants in the body, even though they stimulate antioxidant defenses at all concentrations.  They provide a dubious benefit of unnecessarily heightening defenses with concomitant energy expenditure at low amounts and net damage at higher amounts.

Hakuna Matata and Sip the Tea

Tea Fanatic

I seem to have painted a compromising picture of plants as less than the perfect food.  They are tough and potentially toxic.  Plants clearly don’t like to be eaten and the best that can come of eaten plants is a full belly and a damaged liver.  But if you cook or ferment the plants first and bacteria start to digest and dull the chemical arsenal, plants can be safely and perhaps even enjoyably eaten.  We need not eat just safe meat.  We can also kick back and sip the tea.

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.]