Antibiotics are naturally made by fungi and bacteria to compete for space and nutrients. Antibiotic resistance is a natural defense. Antibiotic resistance has become an issue because we have misused antibiotics and thus increased the exposure of bacteria to antibiotics. 

Medical use of antibiotics to kill pathogens is similar to being shot with your own stolen gun. Although we synthesize and purify antibiotics for human use, antibiotics originate in microbes. Life as a microbe is tough. Conditions in the soil are ever changing. Food and water are scarce. Microbes only move and reproduce if enough water and food are present. The rotting body of a housefly may seem trivial to humans. For microbes, it’s the biggest buffet in Vegas. It’s every microbe for herself and those with any trick up their pili or thallus to feed and divide faster to fill up the habitat space are the winners. Enter toxins that kill bacteria – antibiotics – literally meaning “against” “life”. Bacteria or fungi make and release these toxic substances into the environment to kill their competitors. The microbes making the toxins often protect themselves by targeting cell structures that they don’t have, but their competitors do. Similar to how Superman is weakened by kryptonite, while his arch enemy Lex Luthor is not. The diversity of microbes in our world fighting for limited space and nutrients has led to a vast array of microbially toxic antibiotic substances. Humans have stolen these toxic weapons from microbes to use against bacteria that are harmful to our health.

The Microbial Arsenals

A spoonful of dirt holds about 100 billion microbes, both bacterial and fungal, and their associated arsenals. While your penicillin or vancomycin may come to you in the form of capsules, they were originally isolated from microbes. Before throwing out some old bacterial plates, Alexander Fleming noticed an empty area around a mold where bacterial cells were not growing. He isolated the mold and then its antibacterial weapon – penicillin [1]. That first isolated mold didn’t produce much of the toxin, so after testing many other isolated Penicillium mold strains, scientists finally found one mold strain growing on a cantaloupe that produced an abundance of the antibiotic. That one mold strain is the source of today’s penicillin in your capsules. Vancomycin came from a bacterium found in a bit of soil in Borneo. Each antibiotic in use today was a weapon one microbe used on another. We’ve simply figured out how to produce these toxins in high concentrations and in a purified form for our own uses.

Natural Antibiotic Resistance

With any new weapon on the battlefield comes an arms race. Antibiotic resistance is the arms race in the microbial battlefield. Most of the bacteria attacked will die, but those that are not killed have an advantage over their toxin-producing enemies. Bacteria can change their DNA instructions for the cell structures the antibiotics target leading to a “better body armor”. Bacteria may inactivate the toxin. They may pump the toxin out of the bacterial cell before the chemical toxin hits its target. No matter how antibiotic resistance works or whether other microbes or humans are wielding the weapon, antibiotic resistance gives the microbe under attack an upper hand. The antibiotic resistant microbe can survive, feed, and divide where susceptible bacteria cannot. The more frequently bacteria, or any organism for that matter, are exposed to a particular “danger” there is increased chance that some of the individuals may be different enough that the drug no longer can get into the bacteria or damage the cell structure. To complicate the battlefield more, bacteria can pick up these changes in their DNA from other resistant bacteria. Increased use of antibiotics results in higher doses released into the environment and the more opportunities we provide for antibiotic resistance to occur and spread.

The microbial war for space and food has been raging for eons. The resulting arms race yielding countless diversity of antibiotics and responses to render these toxins ineffective. Warriors from the bacterial battlefield linger around their old campfires lying in wait for another battle. Those original battles may have been fought 30,000 years ago when land that is now under glaciers was green and growing [2]. The battles may have been inside of ancient humans present now in mummies [3]. Natural battles are in wilderness areas in Alaska [4] and isolated caves [5] untouched by human hands. Any time those bacteria and fungi are synthesizing antibiotics in nature to use to defend themselves, the chance of antibiotic resistance and the arms race escalation may occur. These events are the natural battlefields of antibiotic resistance rarely encountered by human pathogens and endangering people, but they are natural reservoirs of antibiotic resistance. A larger threat looms with antibiotic resistance occurring due to human use.

Recent and more problematic antibiotic battlefields are our hospitals and doctors’ offices where antibiotics are used prophylactically or to treat non-bacterial illnesses.  A second human-created antibiotic battlefield are large scale agricultural feedlots where antibiotics are added to feed to promote animal growth. Yet another are homes, schools, and workplaces using antibiotic cleaners and soaps.  The magnitude of antibiotic use in these human-induced battlefields and the concentrations of the antibiotics increases the opportunity for antibiotic resistance to occur. Higher numbers of bacteria routinely exposed to antibiotics increases the chances that these bacteria will change to defend themselves from these toxins. The density of people or other animals living close together provides the increased opportunity for antibiotic resistance to spread from one animal to another.

Antibiotics: Handle With Care

Antibiotics have been our miracle cure for bacterial infections since Fleming isolated that first Penicillium strain in the 1940’s. Disease-causing bacteria that were easily killed decades ago when antibiotics were first used now survive higher and higher doses of antibiotics and a wider range of antibiotics. These “super bugs” elude our strongest antibiotics and can potentially push us into an “antibiotic winter” – a time when antibiotics are ineffective. The bacteria causing tuberculosis and gonorrhea, MRSA, and the emergence of other virulent bacteria that aren’t killed by antibiotics terrify patients and medical personnel alike. This resistance is a warning shot in the antibiotic war between humans and bacteria.

What will be our next move? Isolating new antibiotics from nature is costly and not profitable for private pharmaceutical companies. Funds for basic research in academic and government institutions are being routinely cut. One novel solution is the Small World Initiative, a crowd-sourcing project begun by Dr. Jo Handelsman which trains undergraduate university students to isolate antibiotics from nature. Another solution is to seek out novel alternatives such as interrupting bacterial communication [6] or using predatory bacteria to feed on the pathogens [7]. Until a solution is found, we can attempt to deescalate the arms race by limiting the use of antibiotics to when they are medically necessary to treat bacterial infections. The World Health Organization and others suggest using antibiotics only to treat bacterial, not viral infections, and restricting the use of antibiotics from animal feed as a growth promoter. Better understanding of what antibiotics are, how resistance occurs and spreads, and how to properly use antibiotics is a first step in battle plan.

For more information on World Antibiotic Resistance Week visit the following sites:

The World Health Organization – Antibiotics: Handle With Care

The European Center for Disease Prevention and Control – European Antibiotic Awareness Day

The United States of America: National Strategy for Combating Antibiotic Resistant Bacteria and the President’s Advisory Council.

For related media articles:

Antibiotics in Animal Feed Endanger Kids, Doctors Warn

A Radically Simple Idea May Open the Door to a New World of Antibiotics

REFERENCES

1. Fleming A: On the Antibacterial Action of Cultures of a Penicillium, with Special Reference to their Use in the Isolation of B. influenzæ. British journal of experimental pathology 1929, 10(3):226-236.
2. D’Costa V, King C, Kalan L, Morar M, Sung W, Schwarz C, Froese D, Zazula G, Calmels F, Debruyne R et al: Antibiotic resitance is ancient. Nature 2011, 477:457 – 461.
3. Santiago-Rodriguez TM, Fornaciari G, Luciani S, Dowd SE, Toranzos GA, Marota I, Cano RJ: Gut Microbiome of an 11^th Century A.D. Pre-Columbian Andean Mummy. PLoS ONE 2015, 10(9):e0138135.
4. Allen HK, Donato J, Wang HH, Cloud-Hansen KA, Davies J, Handelsman J: Call of the wild: antibiotic resistance genes in natural environments. Nature Reviews in Microbiology 2010, 8(4):251-259.
5. Bhullar K, Waglechner N, Pawlowski A, Koteva K, Banks E, Johnston M, Barton H, Wright G: Antibiotic resistance is prevalent in an isolated cave microbiome. PLoS One 2012, 7:e34953.
6. LaSarre B, Federle MJ: Exploiting Quorum Sensing To Confuse Bacterial Pathogens. Microbiol Mol Biol Rev 2013, 77(1):73-111.
7. Dashiff A, Junka RA, Libera M, Kadouri DE: Predation of human pathogens by the predatory bacteria Micavibrio aeruginosavorus and Bdellovibrio bacteriovorus. J Appl Microbiol 2011, 110(2):431-444.