THURSDAY, 3 DECEMBER 2020
When penicillin, the first antibiotic, became widely available in the mid-1940s, modern medicine was revolutionised. Small wounds and childbirth no longer resulted in life-threatening incurable infections. Meningitis, tuberculosis, and chronic bone infections could all be cured. Surgery became safer since pre-operative antibiotics lowered the risk of postsurgical infection, allowing longer and more complex operations to be attempted. Disturbingly, the rise of antibiotic resistant strains of bacteria may mean we are entering a ‘post-antibiotic era’ in which antibiotics become practically useless. While there are currently 700,000 antibiotic resistance related deaths per year, this is predicted to rise to 10 million by 2050. The World Health Organization (WHO) is declaring antibiotic resistance a ‘major global threat’ in which ‘common infections and minor injuries which have been treatable for decades can once again kill’. Pandemics of such superbugs could easily result in global quarantines and lockdowns.
Antibiotics Treat Bacterial Infections
Antibiotics are used to treat bacterial infections by interfering with processes that bacteria need to survive and grow such as bacterial cell wall production, protein synthesis, or cell division. On the other hand, viruses are not alive and cannot be killed using antibiotics. This is because viruses cannot reproduce on their own and instead rely on the host cell to make the proteins needed to produce new viruses. This process cannot be inhibited because we are the host — we would be poisoning our own cells. It is our overuse of antibiotics out of convenience which has accelerated the development of antibiotic resistant strains of bacteria. For example, global antibiotic use (average doses per day) increased by 65% between 2000–2015, with low-middle income countries being the main driving force. Further increases are predicted for the period to 2030 in the scenario that no restrictions are introduced.
The Problem Of Antibiotic Resistance
When bacteria face a threat in the form of an antibiotic, it drives evolution for traits that help their survival. Within a population, there is a small chance that some bacteria will harbour a random genetic mutation which allows them to survive exposure to antibiotics. The presence of antibiotics selects for variants containing such a mutation — while the susceptible bacteria are killed, the resistant ones survive, reproduce, and take over the population. This has led to an ongoing evolutionary arms race between our own drug development and bacterial mechanisms to avoid their own death.
Research into new antibiotics has slowed down in recent decades, which aggravates the problem. Antibiotics are classified by their chemical structure, cellular mechanism of action, and the species of bacteria they are effective against. During the ‘golden era’ of antibiotics research (1950–1960s), scientists generally overcame problems of antibiotic resistance by developing new antibiotics at a faster rate than bacteria developed resistance. Half of the antibiotics in use today were discovered during this period. In contrast, no new classes of antibiotics have been discovered since the 1980s.
The process of discovering genuinely new antibiotics and bringing them to market is challenging and time-consuming. It can take up to 15 years. Firstly, organisms which produce antibiotic substances are identified. This can be difficult because these substances must also be non-toxic to humans. Candidate drugs then move into clinical trials to be tested for safety and efficacy. These clinical trials have five stages including further tests on thousands of patients even after the product is approved. According to the WHO, there are 40–50 antibiotics in clinical trials but most of these are just minor modifications of existing drugs and have little additional benefit. 250 novel antibiotics are currently in preclinical trials but it will take at least 10 years for these to reach patients and many may never be approved for use.
It is becoming increasingly difficult to find new bacterial proteins to target. This does not mean there has been no effort on this front. Pfizer, AstraZeneca, and GlaxoSmithKline ran a total of 200 ‘high throughput screens’ during the 1990s but none of these resulted in a viable drug candidate. There is a consensus within the industry that the antibiotics that were easy to discover have already been found and that expensive labour-intensive research would be required to identify new classes of antibiotics. Furthermore, these big pharmaceutical companies have recently lost interest in the development of novel antibiotics, as such drugs would be used as a last resort by only a few thousand people a year. It is not profitable for companies to invest in antibiotic development when they could instead develop drugs for chronic conditions such as asthma or diabetes, which require constant administration and therefore greater sales.
A New Wind In Development
Fortunately, there are some promising developments in the field of antibiotics research. One recently discovered compound, Irresistin, kills bacteria via a ‘poisoned arrow’ mechanism. It simultaneously punctures bacterial cell walls and destroys folate, a compound needed by bacteria to make DNA. Attacking two processes at the same time may make it harder for resistance to develop. This is a concept that will hopefully lead to new types of antibiotics in the future.
Another way to overcome the development of antibiotic resistant bacteria is with novel antibacterial medicines which have different modes of action to conventional antibiotics. Virulence blockers are drugs which effectively ‘disarm’ bacteria of their pathogenicity and prevent them from manipulating host cellular processes. For example, the type III secretion system (T3SS) is used by Gram-negative bacteria to directly inject toxins into host cells to help bacteria invade host tissues or suppress host immune responses. The T3SS can be inhibited by compounds such as salicylidene acylhydrazides, which are currently being trialled as an alternative to antibiotics. Resistance to such drugs could also develop but probably not as rapidly as for conventional antibiotics. The targets of virulence blockers are found in a smaller subset of bacteria so their use will apply selective pressure on fewer organisms and only limit bacterial replication when bacteria reside in the infected host.
Phage therapy is also a promising possibility. Bacteriophages, also known as phages, are viruses which infect and replicate within specific bacteria, ultimately leading to lysis and death of the bacterial host. The idea of using bacterial viruses therapeutically has been around since the 1930s and phages were widely used to treat human patients in the Soviet Union during the Cold War. However, phage therapy has only recently gained traction in other countries due to the need for a response to multi-drug resistant pathogens. For example, in France phage therapy has been approved to treat patients with multi-drug resistant infections. Six patients with such infected burn wounds have been successfully treated. Larger scale clinical studies are required to verify the safety and efficacy of bacteriophages as a treatment for other types of human infections.
Antibodies are proteins naturally produced by our immune systems during infection. Antibodies bind to specific bacterial proteins, inhibit pathogenicity, and make it easier for white blood cells to destroy the bacteria. There has previously been little interest in antibodies as treatment for bacterial infections as widespread antibiotic resistance was not a problem. With the threat of a ‘post-antibiotic era’ looming, antibodies are now being investigated as a viable therapeutic alternative. Monoclonal antibodies are identical copies of one type of antibody, produced from a clone of immune cells. These antibodies can be bioengineered to specifically target the resistant strains of bacteria.
While these alternatives to antibiotics are exciting prospects, it is likely to be several years before any of them are commercially available. For now, we must ensure we are using the right antibiotics at the right time to slow the development of resistance to the antibiotics that still work
Megan Hardy is an MSci Biological Natural Sciences student in Biochemistry at Emmanuel College. Artwork by Marzia Munafo