Microbial Biological Warfare: Antibiotic Resistance

Did you know we might be moving into an era where antibiotics are obsolete? Just earlier this week there was an article in the U.S. News describing an outbreak of ‘Totally Drug-Resistant’ Tuberculosis in South Africa. In light of this increasingly urgent problem, this post is dedicated to antibiotic resistance!

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What is antibiotic resistance?

Antibiotic resistance (AR) is a naturally occurring phenomenon that arises through biological and chemical warfare between microbes. DNA analyses have found proof of antibiotic resistance in 30,000 year old sediment samples, but it’s likely that the battle between antibiotics and resistance has been going on for millions of years [7]. Bacteria and other such organisms are constantly competing for resources (or eating each other), turning the world around us into a slaughterhouse of biological warfare. It’s all very exciting, but most of us humans are completely oblivious to it.

Chemicals that harm other microbes (antibiotics/antimicrobials) are a common weapon in these battles. Microbes that have evolved to produce a certain antibiotic often also have a resistance to the chemical’s effect so that they don’t end up killing themselves in the process. Additionally, resistance arises in the targets over time, as any microbe that has a mutation conveying some resistance to the antibiotic will survive and pass that resistance onto its offspring.

Antibiotics function in a variety of ways, targeting vital processes of microbes to prevent reproduction or kill them. Consequently, there are many different mechanisms for antibiotic resistance. The most common include altering the target of the antibiotic and consequently preventing it from binding and effecting the microbe, efflux or biological pumps that remove the antibiotic from the organism, and chemically modifying the antibiotic via an enzyme that cuts up the antibiotic and renders it useless [6,16]. These defenses can arise through mutations or horizontal transfer (we’ll cover that later!). Resistance can be conferred by a single point mutation (only changing one letter of DNA code), such as high level resistance to some drugs, including quinolones and rifamycin, by changing the structure of the target slightly [12]. Others require more complex, sequential mutations over generations.

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The Problem

Humans were pretty slow on the uptake and only realized we could utilize these natural chemicals as antibiotics in the past 60-70 years [1]. Since their discovery, antibiotics have become the most successful drugs in human medicine. Natural and synthetic antibiotics have saved millions of lives and allowed for incredible medical procedures that would otherwise not be possible [16]. Unfortunately, microbes have had millions of years more experience than us at combating antibiotics, and they’ve become incredibly efficient–especially with our unwitting help.

All antibiotics are subject to resistance, and each comes with a very limited lifespan of use [16]. Humans have always been engaged in a biological war with microbes, but now that we’re actually aware of it, it’s obvious that we’re frighteningly overmatched. In an experiment designed to mimic naturally occurring conditions, scientists discovered that E. coli could gain resistance to the antibiotic ciprofloxacin in under ten hours, through four spontaneous mutations [18]. In Europe in 2007, there were over 400,000 infections by multi-drug resistant bacteria. In the United States, antibiotic resistant infections are responsible for $20 billion per year in health care costs and $35 billion a year in societal costs [3]. Antibiotic resistance is spreading throughout pathogens at an incredible rate, increasing the risk of medical complications and fatalities, economic burden, and threatening to turn antibiotics obsolete [1]. Unfortunately, research combining theory, mathematical modeling, experiments, and clinical intervention all suggest it is an irreversible problem.

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How did we get ourselves into this mess?

Human use and misuse of antibiotics has added a highly selective force for pathogen resistance evolution in the past 70 years. Antibiotic concentrations in the environment are one of the main driving forces for selecting for AR in microbes [1, 7]. It’s estimated that several million tons of antibiotics have been produced worldwide since they were introduced; China alone produced over 210 million kg of antibiotics in 2007 [1,19].  We use antibiotics on ourselves, inject them into livestock, and add them to animal food and water [19]. The antibiotics do not just vanish, either; they pass through animal systems and enter the soil ecosystems and the water environment.

Consequently, the high antibiotic concentrations select for resistance mutations and give resistant microbes an advantage to proliferate. In a swine farm in China, 149 unique resistance genes were found to have evolved in that one location alone, and water screening tests worldwide have discovered antibiotic resistant genes in organisms in hospital waste water, animal production waste water, seawater, water treatment plants, surface water, ground water, and even drinking water [19, 17].

Multi-drug resistance and pathogens with resistances are increasingly a problem due to human abuse and misuse of antibiotics. In ‘sterile’ environments like hospitals, microbes carrying genes resistant to the many types of drugs present have the opportunity to flourish and infect. Hand sanitizers provide a similar situation; they may kill 99.9% of microbes on your skin, but that 0.1% that is resistant will have all their competition eliminated, providing the perfect opportunity to go forth and multiply. Now, many of these microbes may not be pathogenic and won’t cause any problems to your health, but the genes conveying their resistances can spread (see the next section!) [1,7].

In other cases, humans directly enable pathogenic microbes to increase resistance. Consider antibiotic doses: how many people do you know who have prematurely stopped taking their antibiotics because they start to feel better? The problem is that the doses of antibiotics are not arbitrary; they’ve been carefully calculated to ensure the complete eradication of the infectious agent. What is actually occurring as you take your antibiotics is illustrated in the figure below. Resistance varies between strains and members of a species. The first couple doses will wipe out the vulnerable members. Subsequent doses will override the more resistant members contributing to your infection. However, if the antibiotics are stopped prematurely (often because the patient feels better or the side effects are horrible), the most resistant strains of pathogens are left and will be able to proliferate. This can cause a second infection, which is much more difficult to treat. Tuberculosis is perhaps the best known example, with reoccurring infections becoming multiple, or totally, drug resistant [1,11, 12]. Resistance in some Salmonella and E. coli strains have also been detected, as well as the infamous MRSA hospital infection, Acinetobacter baumanni in intensive care units, Helicobacter pylori which infects over 90% of adults in developing countries such as Egypt, and even leprosy which still occurs in over 200,000 people each year [3,5,6,8,14]. These, and dozens of other pathogen-caused diseases, are rapidly gaining multiple drug resistances.

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How is it spreading?

Antibiotic resistance wouldn’t be an overwhelming problem if the cases and resistant microbes were isolated. Of course, we’re not that lucky! The main problem with AR is the ability of it to move through and between species. Resistance mechanisms are carried on genes, sections of DNA that code for specific proteins. These genes often exist on mobile genetic elements; pieces of DNA that can self replicate, insert into genomes, and even exit cells and infect other cells. Plasmids, viruses, and transposons are just a few examples [5]. Once a microbe has a resistance gene (or genes, as the case may be), it will pass that resistance to its offspring (often clones, in the case of microbes) and so on and so forth, rapidly spreading through a population. This is called vertical transmission, from generation to generation.

Microbes also undergo horizontal transmission. The mobile elements containing resistance genes, or resistance islands if there are a cluster of genes together, can actually move between unrelated species of microbes. Microbes undergo conjugation, where one will extend a tube into another microbe through which DNA passes and can become integrated into the second organism. They also pick up DNA from the environment around them, ejected or left over from dead microbes, which is called transformation. Finally, viruses can inject an organism with DNA in a process called transduction. As resistance genes have become more and more common due to the recent selective pressures, horizontal transmission through these methods have allowed the resistances to pass through microbial species and pathogens. Furthermore, as resistance genes often cluster together on resistance islands, one single horizontal transformation event can result in multiple drug resistances [5,10,2]!

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NMD-1

An example of this rapid spread of antibiotic resistance is the New Delhi metallo-beta-lactamase, which is more commonly known as NMD-1. This is a gene that codes for an enzyme which breaks down almost all groups of antibiotics, including penicillin [3,4,9]. NMD-1 is carried on a large plasmid, which is a circular piece of DNA that easily undergoes horizontal transmission and rapidly spreads between species and pathogens. It was first reported in New Delhi (hence the name) in 2007, however since then it has spread and been reported in all continents and dozens of countries, including the USA. It has entered some strains of E. coli, K. pneumonia, A. baumanni, Vibrio cholerae, and dozens of other pathogens as it passes horizontally in hospitals and has been found to be common in tap water in New Delhi [3,4,9,13].

 

What can we do about it?

Now that I’ve hopefully terrified you into always finishing your antibiotic prescriptions…what’s the outlook? Scientists seem to agree that there is nothing we can do to eliminate resistance or reverse the situation, as classical measures to try and halt the progress of AR are insufficient against the global rise of resistance [2]. However, some believe it can still be controlled or alternative treatments can be found. Most resistances are not total, so a cocktail of drugs are used to treat the diseases (leprosy and tuberculosis being prime examples). With the emergence of total resistance in some strains of disease, things get a little more complicated.

New types of drugs and alternative treatments are hot on the research list. Scientists are beginning to explore the idea of drugs that try to prevent the spread of resistance, and even perhaps restore susceptibility, by taking ecology and evolution into account. Rather than aiming to kill, these theoretical drugs are focused toward preventing the emergence and evolution of resistance, or even giving non-resistant strains an advantage so they can repopulate [2]. The mechanisms behind these are still being pondered, but it’s an exciting new direction of focus. Research is also moving toward targeting the resistance mechanisms, such as the efflux pumps, which would then allow antibiotics to be used successfully [16]. Also on the horizon of research are alternative treatments such as antibacterial vaccines, immunostimulants, phage therapy, and probiotics (use microbes to fight your battles for you–after all, we’ve discovered they’re better at it!)[3].

Other approaches to this problem include tighter prescription regulations, to try and prevent the antibiotic abuse that occurs, and screening patients that come into hospitals for multiple drug resistant bacteria to help prevent the spread of genes like NDM-1. Finally, public education is always important; far too few people understand the impact bacteria and antibiotics have in our lives, and consequently use antibiotics improperly. Several education programs have already been created, including one in Europe that’s humorously called e-Bug, and other people like me simply write blogs about it in secluded corners of the internet [3,9].

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Cartoon by Nick D. Kim

References

 [1] Andersson, D. and Hughes, D. “Persistence of antibiotic resistance in bacterial populations.” FEMS Microbiol Rev. 2011. 35:901-911.

[2] Baquero, F., et al. “Ecology and Evolution as tarets: the need for novel eco-evo drugs and strategies to fight antibiotic resistance.” Antimicrobial Agents and Chemotherapy. 2011. 55(8):3649.

[3] Bush, K., et al. “Tackling antibiotic resistance.” Nature Reviews. 2011. 9.

[4] Chen, Y., et al. “Emergence of NDM-1-producing Acinetobacter baumannii in China.” J Antimicrob Chemother. 2011. 66: 1255-1259.

[5] Colomer-Lluch, M., et al. “Antibiotic resistance genes in the bacteriophage DNA fraction of environmental samples.” Plos One.2011. 6(3).

[6] Coyne, S., et al. “Efflux-mediated antibiotic resistance in Acintobacter spp.” Antimicrobial Agents and Chemotherapy. 2011. 55(3):947.

[7] D’Costa, V., et al. “Antibiotic resistance is ancient.” Nature Research Letter. 2011. 477.

[8] Iwanczak, F. and Iwanczak, B. “Treatment of Helicobacter pylori infection in the aspect of increasing antibiotic resistance.” Adv Clin Exp Med. 2012. 21(5):671-680.

[9] Nordmann, P., et al. “Does broad-spectrum beta-lactam resistance due to NDM-1 herald the end of the antibiotic era for treatment of infections caused by gram-negative bacteria?” J Antimicrob Chemother. 2011. 66:689-692.

[10] Partridge, S. “Analysis of antibiotic resistant regions in Gram-negative bacteria.” FEMS Microbiol Rev. 2011. 35:820-855.

[11] Koebler, J. “Doctors struggling to fight ‘totally drug-resistant’ tuberculosis in South Africa.” U.S. News. 2013.

[12] Toprak, E., et al. “Evolutionary paths to antibiotic resistance under dynamically sustained drug selection.” Nature Genetics. 2012. 44(1): 101-106.

[13] Walsh, TR., et al. “Dissemination of NDM-1 positive bacteria in the New Delhi environment and its implications for human health: an environmental point prevalence study.” Lancet Infect Dis. 2011. 11(5):355-362.

[14] Williams, D. and Gillis, T. “Drug-resistant leprosy: monitoring and current status.” Lepr Rev. 2012. 83:269-281.

[15] Woodford, N., et al. “Multiresistant Gram-negative bacteria: the role of high-risk clones in the dissemination of antibiotic resistance.” FEMS Microbiol Rev. 2011. 35:736-755.

[16] Wright, G. “Molecular mechanisms of antibiotic resistance.” Chem. Commun. 2011. 47:4055-4061.

[17] Zhang, Q., et al. “Acceleration of emergence of bacterial antibiotic resistance in connected microenvironments.” Science. 2011. 333:1764.

[18] Zhang, X., et al. “Antibiotic resistance genes in water environment.” Appl Microbiol Biotechnol. 2009. 82:397-414.

[19] Zhu, Y., et al. “Diverse and abundant antibiotic resistance genes in Chinese swine farms.” PNAS Early Edition. 2012.

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