Author: Julia Busch Edited by: Luiz Guidi
Not too long ago infectious diseases where the plight of humanity. A high fever was almost a death sentence, and any birth or surgical procedure carried an enormous risk of complications through infections.
But In 1928, Alexander Fleming discovered a compound he called penicillin. It was to change the world of medicine forever. In the war against disease, humankind suddenly had the advantage. It took a decade until the world realised the impact of this discovery. World War II saw the first widespread use of this antibiotic to treat wounded soldiers and what a difference it made. It seemed to beat a major human predator that was capable of keeping the population at check.
Since penicillin, about 100 antibiotic compounds have been discovered. In the developed world, there is probably no one who has not had a course of antibiotics in their lifetime. Even though this miracle fell into our hands less than a century ago, its success has gifted us with a sense of security when it comes to bacterial infections. In fact, our trust in antibiotics has grown so big that we do not remember the fight against infection, we do not know what it must have been like to be helpless against bacteria, to rely on our immune system and painkillers alone to ward off deadly inflammations.
Antibiotics are as common as aspirin, routinely prescribed, all too often consumed unnecessarily. This sense of security is false and has been from the very beginning. Our careless treatment of this accidental miracle puts us on the brink of a new dark age of medicine as bacteria are fighting back.
What we have taken for granted was not a human invention – but merely a discovery of compounds that bacteria and other microorganisms have been using for ages to win little advantages in the eternal struggle for space and nutrients. We believed that the war was won, but when it comes to antibiotics we are fighting on the enemies’ turf. Antibiotic resistance is not just the buzzword of the century, it is as old as bacteria themselves, who have evolved to develop, refine and transmit resistance.
Unfortunately, what might be portrayed as a shocking surprise for the healthcare system has, in fact, been a long time coming. Resistance to penicillin was recorded as early as the mid 1940s. In 1960, cases of resistance were rampant. The first multi-resistant bacterium MRSA (methicillin resistant staphylococcus aureus) was discovered in 1961, a strain resistant to all beta-lactam antibodies. This was just the beginning of the dawn of antibiotic resistance.
Another prominent re-emergence of a disease linked to multi-drug resistance is tuberculosis. Almost eradicated at one point from the mind of people in the developed world, now strains of the bacteria resistant to all first and second line antibiotics are on the rise in several countries. In 2013, the Center for Disease Control (CDC) released a list of bacteria of concern, categorising the most troublesome emergences of resistant bacteria into three hazard categories: urgent, serious and concerning. As of 2016, twelve diseases, including tuberculosis, fell into the serious category and pose significant threat of developing into urgent problems without further investment into prevention. Urgent public health threats are those bacteria with even higher resistance to antibiotics that might not yet be widespread, but have the potential to become uncontrollable risks. This category already includes Colstridium, causing a quarter of a million infections per year, carbapenem-resistant Enterobacteriaceae (CRE) and drug resistant gonorrhea. It is likely that the number of diseases categorised as urgent threats will rise.
As bacteria are starting to gain ground, the discovery rate for new antibiotics has stalled.
Overall, currently used antibiotics can be sorted into four categories based on their point of attack within the bacterium. The mechanisms targeted are cellular pathways unique to bacteria. The effects of the compounds are by design directed at bacterial cells only. Despite that, some antibiotic classes carry severe side effects, leading to heavy overuse of safer antibiotics. The requirement of drugs to only hit targets characteristic to bacterial cells, but not harm human cells, limits the pool of possible new targets for future antibiotics. This is a disadvantage for future discovery that further enhances the problem of antibiotic resistance.
Bacteria have ways to survive attacks. Resistance mechanisms include enzymes that can inactivate the attacking chemical compound directly, protective mutations in the antibiotic target and even pumps that excrete the antibiotics from the bacterial cell before they can take effect. They also have ways to communicate their evasive advantage to other bacteria through transfer of genetic material. Their high growth rate coupled with evolutionary pressures allows them to adapt quickly through mutations that give them an evolutionary advantage, allowing for new forms of resistance to emerge.
The incorrect use of antibiotics by patients and overprescription is not the only source of overuse. Low doses of antibiotics given to farm animals to promote muscle growth has been banned in many European countries since the 1970s when this practise was associated with an increase in bacterial antibiotic resistance. However, this method of enhancing meat production is still in use in most of the world. In 2013 the FDA has released a guidance (#213), which advises fading out of the use of medically important antibiotics until 2017.
Can a post-antibiotic era be prevented?
In recognition of this spiralling global problem, the UN met to discuss the state of antibiotic resistance and possible solutions in September 2016. The resulting paper agrees with a proposed plan of action published by the World Health Organisation in 2014.
A part of the problem is to be tackled by increasing training of the public and healthcare professionals on the use and prescription of the drugs. At the same time, antibiotics that are not yet associated with widespread resistance are to be limited to emergency uses.
The efficiency of some antibiotics can be supported by the additional treatment with inhibitors for the resistance mechanism. Furthermore, development of resistance can potentially be fought with antibiotic cocktails that target several bacterial weak points.
While these measures are necessary to stall the development of further resistance, new approaches and ideas are needed to bring us to a position of continued protection.
The road to securing our continued lead in the fight against bacterial resistance is stony, and added difficulties stem from very worldly problems. The pharmaceutical industry has been facing a crisis for the last decade, which has led to restructuring of research foci. Fighting for their financial survival, antibiotics and antibiotic research- an area where new hits are increasingly unlikely to be generated and with traditionally low-priced finished products - have not been priorities in the industry’s research agenda, as they represent high risk-low gain investments.
As a result, the challenge is left to academic research and industry collaborations to bring fresh ideas into this dire situation. The last few years have seen several advances that raise hope in the approach from academia - where even the most obscure sounding ideas have a chance to blossom and develop into our saving grace.
In essence, the discovery process for modern antibiotics is not different from how Flemming discovered penicillin, since synthetic approaches to antibiotic discovery have not been successful. Trusting the brilliance of evolution, natural habitats of bacteria are screened for antibiotic substances produced by competing microorganisms. Most new antibiotics have been found in cultured microorganisms from soil samples. Given that only 1% of microorganisms are cultivable with current methods, there is a huge number microorganisms out there we have not tapped into yet and they can potentially produce antibiotics. This revelation precisely led to the discovery of one of the truly novel and potent antibiotic compounds: teixobactin. This discovery emerged through an innovative technique that allowed researchers to grow previously uncultivable bacteria and it creates promise of the discovery of more lead compounds in the future.
A further promising novel antibiotic substance, lugdunin, was discovered in 2016. It was thanks to scientists’ curiosity about the lack of Staphylococcus aureus in specific samples of human nasal microbiota and their inspiring out-of-the-box thinking that led to the discovery. Venturing even further into the unknown, some researchers have discovered that fungi growing in the fur of wild sloths contain natural compounds with antibiotic properties. Other approaches are focused on age-old remedies like honey, which has been valued for its wound healing properties in ancient Egypt and earlier, but its active ingredients remain mysterious. In the search for ever-new antibiotics, these creative approaches might just be what the doctor ordered.
Small molecule and peptide antibiotics are currently the best weapons against bacteria but, even though we might be able to find new versions of them and utilise them yet a little longer, we are still like Alice and Queen of Hearts: constantly running only to remain in the same spot. To get a step ahead of the game again, we might want to consider yet other possibilities. Phage therapy, for example, has been of some interest for years. The idea is to use bacteria's own natural predators to hunt them down. Developing resistance to a small molecule is easily achieved by little adjustments to the drug target. Fending off a highly selective and much more complex phage, however, is not so easily done. Even though some cases of success have been recorded for experimental phage therapy, until recently the redesign of phages for medical purposes has been a difficult endeavour. The emergence of the CRISPR/Cas9 system as an easily accessible research tool gives us the ability to edit genes more easily than ever before and might be just the tool that makes recoding phages for conventional therapy attainable.
Finally, the ultimate protection against bacterial infection might simply be our own immune system. Nothing is as capable as our bodies at recognising and eradicating previously encountered pathogens. Widespread immunisations and the development of new vaccines will help relieve the burden on antibiotics one disease at a time.
As we protect the status quo with the necessary policies and strengthen our position with new antibiotic compounds, innovative technologies and vaccines, it is imperative to remain conscious of our limited knowledge about nature. Even though we have come a long way since Alexander Flemming and our understanding of diseases and their possible cures is astounding in comparison, we will likely never fully comprehend the intricate mechanisms that contribute to the emergence of resistance. Knowledge is power and identifying unknown details of the workings of nature will help design strategies for disease and resistance prevention.
The use of antibiotics has saved countless lives. We might not remember what the world was like without these miracle drugs, but we might be on the brink of revisiting a pre-antibiotic time. We need to start valuing this tool more and accept that maintaining the lead we have in this race against evolution will take constant effort and innovation. Policy makers, researchers and pharmaceutical companies are beginning to pick up the challenge. However, this is an issue everyone can contribute to by responsibly handling one of the last century's greatest gifts to human health.
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