Wednesday, June 25, 2014
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.
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.