Every now and then, news headlines report on findings of new antibiotics, such as “Maple Syrup Can Kill Superbugs”. Often they are portrayed as ”new”, ”potent”, ”killing superbugs” or having ”no resistance development”. Just reading the headlines, you would be forgiven for thinking the antibiotic crisis is close to being solved. But this is not the case.
Drug development is a long and difficult process, and many promising compounds fail long before they reach the market. All new drug candidates undergo rigorous testing in a wide array of laboratory tests, animal testing and last, but not least, clinical trials in humans. Many new compounds showing potential in the early discovery phases fail during this process. There are two major challenges in antibiotic drug discovery that are often overlooked and lead to failure:
- Getting the antibiotic into the bacteria, and making sure it is not immediately pumped out.
- Finding a compound that kills the bacteria without killing the patient.
Below we take a look at some substances that have made the headlines in recent years:
In 2014, the American Chemical Society published a press release entitled “Honey is a new approach to fighting antibiotic resistance: How sweet it is!” Honey has been used against infections for millennia, but now the researchers predict it could be even more useful as it’s components are being better understood. How it has been used has varied from time to time and between cultures. In contemporary medical use, honey is sometimes used on skin e.g. to treat wounds and burns. The effect of honey is ascribed to many different factors: peroxide formation, antimicrobial peptides and probiotic Lactobacilli that dwell in the honey are some of the most common. While clinical trials have shown some beneficial effects of honey, no drug candidates have emerged from this research.
Teixobactin was headlined in Nature in 2015: “Promising antibiotic discovered in microbial ‘dark matter’”. It is a naturally occurring antibiotic produced by a species of bacteria living in soil. Many other antibiotics have been found in in the past by studying soil bacteria, but that line of research had all but dried up until recently. When the discovery of teixobactin was announced, headlines stated that it was a new class of antibiotic and that it had no development of resistance. Unfortunately, both of these assertions are so far attached with some level of uncertainty.
Teixobactin works in a similar manner as another already existing antibiotic, vancomycin. However, teixobactin acts on part of a cell wall component that cannot be easily changed without causing lethal damage to the bacterium itself. As the chance of finding a functioning mutant decreases, hopes are that resistance to teixobactin is more difficult to acquire. Resistance development may not have been observed in initial experiments yet, but similar beliefs for e.g. vancomycin, have been proven wrong. As of yet, teixobactin has not yet reached testing in clinical trials.
Perhaps more interesting than the compound itself, was the technology used to discover it. Using the so-called iChip, researchers are now able to culture bacteria that previously have been impossible to study in a laboratory due to their requirement of a complex environment that has been impossible to reproduce. The iChip however reproduces such environments. As it is believed that many unculturable soil bacteria may produce antibacterial substances, this technology opens possibilities for discovery of new drug candidates.
The discovery that compounds called phenols in maple syrup could enhance the action of antibiotics was communicated under the headline “No more ‘superbugs’?” in a press release from the American Chemical Society. The article described that researchers has found that the maple syrup had a sensitising effect on the tested bacteria to the commonly used antibiotic ciprofloxacin. It is proposed to act by increasing the permeability of the bacteria and by inhibiting bacterial pumps that would remove antibiotics from the bacteria.
While these are indeed interesting discoveries, it would still take several years for the discovery to result in a drug. Likely, any drug development based on maple syrup phenols would require identifying which of the components of the extract is most potent, rather than using the whole extract containing a multitude of compounds. Other natural products that have seemed promising at the point of discovery have failed at jumping through all the hoops to show efficacy and safety resulting in discontinued projects.
Rocky roads ahead
Common for all these news are that they are generally released very early in the discovery phase. While such breakthroughs are of course positive, the reality is that most “headline news” regarding promising novel antibiotics are a long way from being an actual antibiotic that can be used in clinical practice. The drug development process from candidate to approved drug can take 10-15 years, and failure rates are particularly high in the early discovery and development phases – in fact compared to all drug classes, antibacterial drugs have about a ten-fold lower yield in the initial stages of R&D. Causes for failure often include poor efficacy in vivo – i.e. when tested in animals or humans – and high levels of toxicity.
To overcome the formidable scientific bottleneck that exist at the early research stages there is first a need for both the public and private sector to invest much more than what is currently being invested today. Such resources should also enable strategic transformation of the R&D full ecosystem. One way could be to target investment and incentives towards much more collaborative approaches – for example by building innovation platforms that engage a more diverse group of researchers from different fields of research to embark on finding new classes of antibiotics yet undiscovered by conventional means.
Article about honey: Honey is a new approach to fighting antibiotic resistance: How sweet it is!
Article about Teixobactin: Promising antibiotic discovered in microbial ‘dark matter’
Article about maple syrup: No more ‘superbugs’? Maple syrup extract enhances antibiotic action.