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.

Paradoxical Inflammation

Anti-inflammatory Treatments Cause Inflammation in Some Diseases, e.g. Rosacea

I thought that the anti-inflammatory diet and lifestyle I outlined on this blog would be a general purpose starting point for the treatment of all diseases. Inflammation is the foundation for allergies, autoimmune diseases and cancer. Inflammation is a basic defense against infectious diseases and many tissues require signaling components integral to inflammation for their normal function, so it is possible to overdo anti-inflammatory treatment and produce immuno-suppression. But that is unusual. What I am talking about here is inflammation caused by vitamin D, omega-3 oils, potentially low carbs and inhibitors of NFkB, such as tumeric. This is Paradoxical Inflammation.

Rosacean Inflammation Is Paradoxical

The obvious example of a paradoxical inflammatory disease is rosacea. Rosacea seems to be a large group of diseases that manifest in facial inflammation. Excessive flushing of the face can become persistent and form pustules and swelling. The triggers for rosacean inflammation are legion and idiosyncratic. They include mundane social interactions, numerous foods, temperature extremes and, paradoxically, just about everything that I recommend to decrease chronic inflammation.

Bacteria in Tissue and Gut Biofilms Are Candidates

Why do otherwise anti-inflammatory foods and exercise make rosaceans red in the face? Even vagal stimulation that is uniformly calming to inflammation, can make a rosacean flush. This is very inconvenient. I can only invoke the typical players: cryptic bacteria, biofilms, vagus nerve stimulation and response, lymphocytes/macrophages, cytokines and neurotransmitters.

All rosaceans have demonstrated facial inflammation and have had long term exposure to antibiotics and NSAIDs. That combination suggests that bacteria have been transported from a leaky gut (NSAIDs) to the site of inflammation (the face). It is likely that cryptic bacteria inhabit the dermis near the blood vessels and resident lymphocytes/mast cells. This is also the location for axons from vagus nerves. Thus, vagus stimulation may result in the release of neurotransmitter acetylcholine to stimulate lymphocytes/mast cells with subsequent release of cytokines. In this case the cytokines are inflammatory.

Other sources of inflammatory cytokines are lymphocytes/mast cells activated by endotoxin release from cryptic bacteria triggered by immunological attack. In this case, the immunological attack can be initiated by disruption of the stasis invoked by the cryptic bacteria.

Activated Cryptic Bacteria Are Source of Inflammation

It is hypothesized that the cryptic bacteria remain in tissue, because they are able to induce a hibernation-like physiology in the tissue. Disruption of the hibernation would initiate an immunological assault. Disrupting agents typically include vagal stimulators, such as activators of the hot or cold sensors, e.g. capsaicin, castor oil or menthol. Interestingly, the cryptic bacteria require a residual level of inflammation to acquire nutrients from the host. Anti-inflammatories that inhibit NFkB may destabilize the bacterial/host interaction and result in an immunological attack on the bacteria. All of the attacks on the cryptic bacteria release inflammatory endotoxin.

Gut Biofilms Store Bacteria Recruited to Become Cryptic in Inflamed Tissue

During the course of the disease and following numerous antibacterial treatments, bacteria can be continually recruited from safe havens, such as gut biofilms. Antibiotic treatment of biofilms converts the biofilm community to antibiotic resistance through activated horizontal gene transfer. Moreover, harsh treatment of biofilm communities initiates shedding of bacteria that could migrate across the leaky gut adjacent to the gut biofilms and provide new emigrants into the inflamed face tissue. A likely resident would be Chlamydia pneumonia, which has been demonstrated to be carried by macrophages and offloaded at distant sites of inflammation.

How the Vagus Becomes Inflammatory

This brings up the question of why vagal stimulation shifts from anti-inflammatory to inflammatory in rosaceans. I don’t think that the vagus nerves change in either their activation or in the neurotransmitters that are released as a result of stimulation. This means that the cells that respond to the vagal acetylcholine must be changed. I think that the change is a depletion of Treg cells and the result is that acetylcholine receptors on the remaining T cells cause a release of inflammatory cytokines. These cytokines cause the release of NO by endothelial cells and vasodilation. Leaking of endotoxin from the resident cryptic bacteria causes persistent dilation and restructuring of the vasculature.

Helminth and Il-2 Therapy Reestablish Tolerance and Reverse Vagal Inflammation

Since I have been forced to explain paradoxical inflammatory diseases, I might as well speculate on exotic approaches that already suggest potential treatments. Ingesting parasitic worm eggs (helminth therapy) has proven successful in the treatment of inflammatory diseases such as asthma, allergies and IBDs. Interleukin 2 (Il-2), usually used as a complex with an anti-Il2 antibody, is also a productive treatment. In both of these cases, the treatment stimulates the proliferation of Treg cells, which appear to be deficient in many of the inflammatory diseases. These treatments should also lead to a lowering of inflammation in the gut and suppression of inflammation as a result of vagal stimulation. Inhibitors of acetylcholine receptors, e.g. scopolamine patches, might also be interesting to test to see if they inhibit rosacean flushes in response to typical vagal stimulants such as castor oil or menthol.

Addendum:  Another possibility associated with the heavy use of antibiotics by rosaceans is intestinal (biofilm?) candidiasis.  Yeast infections are common after prolonged antibiotic treatment.  Interestingly, Candida produces resolvins from omega-3 fatty acids and the resolvins suppress neutrophil activity that would attack the yeast.  Thus, many of the anti-inflammatory treatments would actually aggravate yeast infections and contribute to rosacea.  Treatment for candidiasis (keeping in mind that yeast may be protected by biofilms) helps many rosaceans.  Stripping biofilms may be useful if pro- and pre-biotics are used to displace Candida.

Suffering from Inflammation?

How do you know if your symptoms result from inflammation?

My interest is the molecular basis of inflammation, how inflammation is triggered and how inflammation contributes to numerous diseases. I try to expose the inflammatory underpinnings of various diseases by initially linking a disease to inflammation and then unraveling the molecular events that lead to and make up the disease.

How Do I Link a Disease to Inflammation?

My first task is to check the biomedical literature to see if there are research articles that support anti-inflammatory interventions that prevent or limit the disease. I just do a PubMed search the disease name plus anti-inflammatory treatments, e.g. omega-3 fish oils, vitamin D, NSAIDs, etc. It is also possible to see if a disease, such as diabetes, that produces chronic inflammation is a risk factor for the new disease being examined. It is shocking to me that omega-3 fish oils (EPA/DHA) or even flax seed oil, have been found to be effective treatments for numerous diseases that range from allergies, arthritis, inflammatory bowel diseases, depression and even septic shock and multiple organ failure. Aspirin has been used to treat infertility and post partum depression, and at high levels to treat cancer.

Dietary Suppression as Prima Fascia Evidence of Inflammatory Cause

If I find that omega-3 oils have been used successfully to treat a disease, then I attempt to link inflammation to the molecular events that initiate the disease. The biomedical literature is of minimal help here. [Biomedical research is usually limited to assessing the impact of drugs on the symptoms of diseases, so the biomedical literature typically does not provide information on the cause of diseases or ways to cure diseases. Causes and cures do not receive research funding.] I have to learn the basic workings of the organs involved and the alterations of function associated with the disease. I have also found by long experience, that major molecular components are systematically missing from typical explanations of function.

Heparan sulfate/heparin Is Missing in Action

Heparan sulfate proteoglycans (HSPGs) dominate the extracellular environment and yet they are systematically excluded from biomedical research. On this blog, I have provided dozens of examples of the essential role played by HSPGs and disruption of these roles by heparin. The majority of cytokines, growth factors, clotting events, complement cascades and even lipid transport (LDL) act via HSPGs. Leaking of proteins into the urine, across the intestines or the blood brain barrier is controlled by HSPGs, is reduced by inflammation and can be partially repaired by heparin. Autoimmune and allergic diseases are initiated by disruptions in HSPG metabolism. Viral and bacterial pathogens bind to human cells via HSPGs. Cancer cells reduce their HSPGs and start to secrete heparanase in order to metastasize. Mast cells secrete heparin! HSPGs and heparin are major players in tissue function and yet the major cell biology text book does not even discuss them. HSPGs are not mentioned in medical school training even though heparin is the most commonly administered drug.

One of the insights that I bring to my conceptualization of diseases is the role of heparan/heparin in cellular physiology. It explains a lot.

Check for Inflammatory Symptoms by Trying the Anti-Inflammatory Diet

If your symptoms are due to inflammation, there is an easy way to find out. Since diet is the biggest source of inflammation and most of the cells of the immune system congregate in your intestines, it makes sense to check to see your health problems are rooted in inflammation by making simple changes in your diet. Since this is just a test, don’t worry about whether or not this is diet for the rest of your life. Just stick to it for a week and see if it changes your life.

The Basic Anti-Inflammatory Diet and Lifestyle Guidelines are here.

(Vitamin D and omega-3 fish oil amounts are minimal levels. More severe examples of inflammation will require higher levels. Vitamin D up to 10,000 IU per day has been found safe. Some individuals require up to 12 fish oil capsule per day to experience relief from symptoms. Increases should be gradual over weeks of time.)

Try it for a week and let me know if your symptoms disappear. The prevalence of diet-based inflammation, makes me confident that you will be glad that you tried these simple, healthy changes. For immediate relief of pain, see my articles on capsaicin, castor oil and menthol/Vicks.

This is not medical advice and is used only in appropriate support of primary medical care.