Resisting Antibiotics – Time for an Antibacterial Revolution?
It was in 1928 that the first antibiotic, penicillin, was discovered by Alexander Fleming. The discovery was a major breakthrough in modern medicine, and penicillin became mass-produced for clinical use by the 1940s. However, it rapidly became apparent that some bacteria were able to evade the effects of penicillin. It was eventually discovered that these bacteria could produce an enzyme that disrupts the chemical structure of penicillin, rendering the antibiotic ineffective. Antibiotic resistance had arrived.
Fleming’s discovery quickly led to the so-called “golden era” of antibiotics in the 1950s and 1960s, where the majority of modern-day antibiotics were discovered. Importantly, during this period, many different classes of antibiotics were identified. These classes were separated based on mechanisms of action i.e. the different ways in which the antibiotics kill or stop the spread of bacteria at the molecular level.
Despite the rapid initial progress in antibiotic development, since the 1960s, only a handful of new antibiotics have been developed. This is perhaps unsurprising - developing a new antibiotic is time-consuming and expensive, coupled with the fact that the science behind developing a new antibiotic is complicated. Moreover, most of the new antibiotics that have recently been developed are in the same class as those that already existed. In such cases, whilst the new antibiotics may demonstrate slight improvements, ultimately, they work using the same mechanism of action. This is important because bacteria that develop resistance to a particular class of antibiotic are more likely to develop resistance to another antibiotic in the same class. As a result, without the development of new classes of antibiotics, antibiotic resistance poses an increasingly serious threat to the treatment of bacterial infections. Indeed, the WHO considers antimicrobial resistance to be one of the top 10 global public health threats. It is no surprise, then, that researchers are looking to identify new ways to fight bacterial infections.
Antimicrobial peptides (AMPs)
One promising alternative to antibiotics is antimicrobial peptides (AMPs). AMPs are small peptides that can bind to the surface of and eventually lyse bacterial cells.
The advantage of AMPs over antibiotics is that they are much less likely to induce resistance. One reason for this is thought to be because AMPs act on multiple targets on bacteria. Specifically, they act on multiple targets on bacterial cell membranes and subsequently multiple intracellular targets. In contrast, antibiotics usually target a single molecular pathway. Bacteria are therefore much more likely to develop a mutation that can provide resistance to that one pathway, compared to developing multiple mutations that would be needed to develop resistance to the effects of AMPs.
The problem with most AMPs, however, is that they are unstable in blood. In particular, they are very susceptible to degradation by proteases (enzymes that break down proteins) present in the blood. What this means in practice is that AMPs can break down before the intended effect of killing bacteria is achieved.
Efforts are ongoing to try and improve AMP stability. For example, researchers at Chalmers University of Technology in Sweden have cross-linked AMPs to hydrogel particles (composed of triblock copolymers), and were able to show that these AMPs retained antibacterial potency for significantly longer compared to free AMPs. A strong antibacterial effect was even shown against methicillin-resistant Staphylococcus aureus (MRSA), which has classically been harder to treat due to antibiotic resistance. It though remains to be seen whether these findings will translate to clinical practice.
Bacteriophages and lysins
Another appealing alternative to antibiotics is the use of bacteriophages: viruses that can infect bacteria. Bacteriophages are able to insert their genetic material into host bacteria and hijack the bacteria’s own cellular machinery. This allows bacteriophages to replicate copies of themselves and ultimately break down the bacterial cell wall (using enzymes called lysins), releasing new bacteriophages ready to attack neighbouring bacterial cells. In this way, bacteriophages can be used to rapidly kill bacteria.
A more direct approach is to administer lysins themselves. Researchers at the Rockefeller University in New York have shown in clinical trials that a lysin-based drug shows significant efficacy against MRSA when administered in combination with antibiotics.
The advantage with bacteriophages and lysins is that they are highly selective for the bacterium that they infect, and therefore do not affect human cells or gut bacteria. However, this advantage also poses a significant challenge in the context of therapeutics. Given the selectivity, the bacteria infecting the patient must be identified in advance of the treatment. Otherwise, it is anyone’s guess as to whether a particular bacteriophage will be effective or not. The solution here may lie in genetic engineering of existing bacteriophages and lysins, so that they are able to infect multiple bacteria.
CRISPR-Cas9 technology, which has become widely known in the context of genome editing, may also offer exciting potential in the context of new antibacterial strategies. CRISPR-Cas9 represents a relatively recent technological breakthrough that allows precise editing of genome sequences. The theoretical proposition, therefore, is to harness this approach by targeting antibiotic resistance genes in bacteria and modifying them to antibiotic susceptible genes.
This theory has already started to be put into practice. Researchers at the Massachusetts Institute of Technology, for example, have managed to show in clinical trials that removal of antimicrobial resistance genes can re-sensitise bacteria to antibiotics. It will be intriguing to see whether more advances will be made in this field, as they may lead to effective continued use of antibiotics in certain circumstances.
Whilst these new antibiotic alternatives represent exciting research and clinical advances, what is important to point out is that they will likely not completely eliminate the issue of antibacterial resistance. However, the key here is that effective antibiotic alternatives can significantly reduce the rate of antibacterial resistance. This is because when multiple treatments with different mechanisms of action are combined, the probability of bacteria developing resistance to all of the mechanisms is significantly reduced. Furthermore, if resistance does occur, having a variety of treatments available would allow clinicians to switch to an alternative efficacious treatment. This is illustrated above, where MRSA, which is resistant to several widely used antibiotics, is shown to be killed using AMPs and lysins.
Given that modern medicine is heavily reliant on antibiotics, they will not be replaced soon, and perhaps nor should they be completely. Of course, a myriad of scientific, financial and logistical factors also need to align for new treatments to become available on the market, so it may take some time before we see new antibiotic alternatives being used in day-to-day life. However, one thing is clear: developing effective antibiotic alternatives that can complement existing antibacterial strategies will be crucial for tackling what is one of the biggest global health threats today.