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Medicine goes viral
Global climate disruptions, biodiversity crises, “eternal” and generalised pollution… in recent years, the perils caused by humanity – for itself and for the living world as a whole – have been accumulating. At the initiative of the WHO, this list has now lengthened inasmuch as antibiotic-resistant bacterial strains have been designated as an additional threat that must be taken seriously.
According to a publication in The Lancet1 , antimicrobial resistant bacteria may have been implicated in nearly 5 million deaths worldwide in 2019. And a report2 commissioned by the British government in 2014 estimated that this figure could double between now and 2050.
Phages: an ancient discovery
Few solutions are available to hinder this increasingly noisy epidemic. One of them, and the least publicised, consists in using a particular type of virus to fight and eliminate antimicrobial resistant bacteria. Most phages take the form of a head and tail, from the tip of which emerge appendices similar to feet. Bacteriophages are particular in that they only attack certain genotypes of bacteria. Could this constitute an additional weapon for personalised medicine?
Phage therapy (the idea of using viruses to treat people infected by pathogenic bacteria) is not a new concept. Discovered independently in the early 20th century by the bacteriologists Frederick Twort and Félix d’Hérelle, bacteriophages – commonly called phages – were first identified as agents that were able to lyse (degrade) bacterial colonies.
“D’Hérelle was immediately interested in this property, thinking that he might be able to draw benefit from it, notably as a therapy to treat bacterial infections,” reminds Anne Chevallereau, a researcher in the Molecular Microbiology and Structural Biochemistry laboratory (MMSB)3 in Lyon (southeastern France), and member of the Phages.fr Research Group (GDR)4. Thus, long before the advent of antibiotics (in 1944, with the commercialisation of penicillin), microbiologists already had a formidable and highly precise weapon against bacteria, but it was the “chemical weapon” of antibiotics that took precedence over its biological counterpart.
Antibiotics, or “weapons of mass destruction”
“The decline of bacteriophages started during the years 1940-44, when an article published by an American society of physicians stated that there was no proof of their efficacy; indeed, they did not seem better, or were even worse, than antibiotics,” notes Rémy Froissart, scientist in the Infectious Diseases and Vectors: Ecology, Genetics, Evolution and Control (MIVEGEC) laboratory5, in Montpellier (southern France). “We should nevertheless note that in France, bacteriophages were still listed in the Vidal Pharmacopoeia until 1977.”
The researcher, also a member of the Phages.fr, network, explains: “We need to remember that antibiotics are weapons of mass destruction and as such, are particularly effective, even in patients where the identity of the infectious agent is not known.” This class of drugs has helped humanity gain several years of life expectancy, but it has also created a host of increasingly dangerous enemies whose watchword could well be: “What doesn’t kill us makes us stronger.”
Target-specific phages
Today, more than 80 years after antibiotics first became available, Chevallereau points out that “the numbers and prevalence of multi-resistant, pathogenic bacterial strains are forcing and encouraging scientists worldwide to reconsider the bacteriophage approach”. Indeed, in 2017, the WHO published a list of pathogenic agents ranked as a priority for research and development on new antibiotics6.
These agents include Pseudomonas, E. coli, staphylococci, Klebsiella and Acinetobacter; bacterial strains have become the preferred targets for specialists in bacteriophages because although they are highly effective, the antibiotics used against them have a major collateral effect, which is their non-specificity. “By contrast, bacteriophages are extremely specific,” Froissart enthuses. This approach therefore offers a way to practise medicine that has nothing to do with the use of chemical agents such as antibiotics.
“When you resort to bacteriophages, it is essential to know which aetiological agent has caused the disease,” he explains. “And we are increasingly aware that most illnesses are often due to several pathogens.” This has therefore favoured recourse to antibiotics rather than developing bacteriophages, which are only specific to one bacterial genotype at a time.
“A different type of medicine”
“This clearly shows that in Western medicine, which is mainly led by symptoms, all treatments are to some extent implemented blindly,” Froissart adds. “In this setting, physicians can therefore make quite frequent mistakes (for example, the inappropriate prescription, still seen today, of antibiotics to treat viral throat infections), which is not in itself a fundamental problem but undoubtedly demonstrates that the will to turn to phages rather than antibiotics requires a different type of medicine.”
Research on the use of bacteriophages in the context of phage therapy entails long-term endeavour. Certainly, a few phages are applied today as compassionate treatment for patients who no longer have any therapeutic options. But because of their exclusion from the Vidal dictionary, it is now crucial to prove their efficacy once again through the conduct of clinical trials.
The interest of physicians in phages largely correlates to their numerous benefits when compared with antibiotics. Last but not least, because they are specific to their targets, phages cause little toxicity.
An arms race
“Another advantage resides in their ability to self-amplify, which is specific to viruses,” adds Froissart. “There is no need to initiate treatment with a large quantity of phages because they will proliferate in situ over time.” Furthermore, once these viruses have eliminated their target, they do not accumulate in the body but simply disappear, in the absence of targets.
However, in the same way as antibiotics, the use of bacteriophages also tends to induce resistance in the bacteria. Is this a major problem for scientists? Not exactly.
In prey/predator relationships, each side tries to get the upper hand – either to better escape the attacker, or, on the contrary, to better aim at its prey. Thus, since the emergence of life on Earth, scientists have referred to the existence of an “arms race”, and this also applies to phages versus bacteria.
Turning resistance against bacteria
Today, according to both Chevallereau and Froissart, the aim is to identify the different mechanisms of resistance (and hence adaptation) deployed by bacteria when repeatedly attacked by phages, in order to exploit these mechanisms against the bacteria themselves.
The scientists are generally seeking to isolate the phages that specifically home in on certain types of receptor found on the bacterial surface, such as LPS (lipopolysaccharide) receptors. “But we could also try to focus on membrane proteins such as porins, or even efflux pumps,” says Froissart.
However, once phages have been employed to attack a single receptor or protein, the bacterium adapts and finds a way out. This prompted microbiologists to consider a different approach based on resorting to a cocktail of phages to target different receptors or channels in the bacteria. “The question being posed at present is to know whether, in a therapeutic context, several phages should be used simultaneously, or whether they should be administered sequentially, one after another.”
“Evolutionary dead ends”
The scientists seem to favour the latter option, because applying the phages in this way makes it possible to some extent to guide the adaptation of bacteria and hence their fate. That is why studying the resistance of bacteria against phages is so crucial. “We are now using this resistance against bacteria,” explains Froissart. “We can push them towards evolutionary dead ends and thus get rid of them definitively.”
“This approach requires a bacterium to adapt to several phages at the same time, which is generally more difficult. Furthermore, these adaptations – necessary to its survival – can directly impact its physiology,” Chevallereau adds. “For example, if the phage ‘entry’ receptor is a porin or channel enabling the molecules necessary to its viability to enter and exit, such as an efflux pump, then the physiology of the bacterium could be severely disturbed.”
Rethinking the fight against antimicrobial resistant bacteria
Froissart goes even further, proposing an approach combining phage and antibiotic therapy: “What is interesting when you target an efflux pump for example, is that the bacterium will respond by inhibiting the synthesis of this pump. Unfortunately for the bacterium, this absence renders it susceptible to all antibiotics, because it is the pump that enables it to release into its close environment the antibiotics that are threatening it.” In this case, the use of antibiotics at the end of a therapeutic protocol would be a final blow to bacteria that had developed resistance to phages.
“Yet when we propose this, physicians look at us wide-eyed because the basic treatment at present for a bacterial infection remains the use of antibiotics, and none of them would currently use them a posteriori,” observes Froissart. “But if we make a parallel with cancer therapies, then different techniques are actually employed: radiotherapy, chemotherapy, immunotherapy, etc. These approaches are gaining in accuracy and can target the heart of the problem with increasing precision by markedly reducing the size of the cancer cell population.”
The development of phage therapy shows how much we need to relearn and rethink existing medical practice when fighting against antimicrobial resistance. “But it is also a question of infrastructure. For as long as we remain within specialised medicine or compassionate treatments, this approach remains feasible,” the scientist says. “Yet whenever the decision is made to use these treatments for non-compassionate indications, it will be necessary to set up infrastructures that do not yet exist. This also involves considerable reflection and major transformations to our healthcare system. Phage therapy will only have a future in the context of a public service, because typically, we need to produce and select phages on a case-by-case basis.” ♦
See also:
Antifungals and antibiotics have identical resistance mechanisms
Friendly bacteria
Pharmacognosy brings nature to our medicine chests
- 1. « Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis », Murray, Christopher J L et al., The Lancet, vol. 399, n° 10325.
- 2. https://bit.ly/40YKmJD
- 3. CNRS / Université Claude Bernard-Lyon 1.
- 4. https://site.phages.fr (in French)
- 5. CNRS / IRD / Université de Montpellier.
- 6. https://www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-...
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