Before Covid-19 took over the news, health headlines were frequently warning of the growing threat of superbugs. Disease-causing bacteria have been evolving resistance to the antibiotics used to treat infections. Starting with the commonly used first-line drugs, superbugs evolve multiple resistance against more and more antibiotics, until in some cases even the antibiotics of last resort are starting to fail.
Perhaps the best-known superbug is MRSA, a strain of Staphylococcus aureus resistant to drugs including methicillin, but unfortunately there are many others. Clostridium difficile and some E. coli strains are resistant to multiple antibiotics; some Klebsiella pneumoniae are now resistant to the last-resort antibiotic Colistin; and almost half a million people a year may be infected with multi-drug-resistant TB. Beyond bacteria, human health is threatened by antiretroviral-resistant HIV, antimalarial-resistant Plasmodium falciparum and antifungal-resistant Candida auris.
Some superbugs have been linked to agriculture, due to antibiotic use in farmed animals, but agriculture also has resistance problems of its own, affecting the health of plants as well as animals. The Black Sigatoka fungus Pseudocercospora fijiensis threatens the bananas in your fruit bowl but also the starchy plantains that are a staple food in many parts of the world, and some strains are now resistant to all four major chemical classes used to treat fungal infections of plants. Similar resistance to multiple fungicidal compounds is evident for strains of the apple scab fungus Venturia inaequalis, and cereal leaf attacking fungi Zymoseptoria tritici, Blumeria graminis and Ramularia collo-cygni. The fungus Botrytis cinerea, causing grey mould in various fruits and vegetables, has evolved resistance to 15 different classes of fungicides.
Plants also get viruses, some spread by “superbugs” that are literally bugs: insects with needle-like mouthparts that pierce plants to drink their sap, spreading viruses as they go. Myzus persicae, an aphid vector of over 100 plant viruses including Potato virus Y, Soybean mosaic virus and Beet yellows, has evolved resistance to four major insecticide groups.
One Health – healthy people, healthy diets, healthy environment.
The comparison of plant health threats to medical superbugs is not just an interesting observation, but a call to share knowledge between disciplines. The ‘One Health’ approach recognises the links between the health of people; healthy diets, which depend upon the health of crops and livestock; and a healthy environment, which depends upon the health of ecosystems and the planet. For resistance, the links between fields are especially clear. If there is one universal law applying to the control of infectious diseases, parasites, crop pests and even invasive species, it is that any effective control measure against a biological population will impose a selective pressure in favour of overcoming that control measure. An antibiotic or pesticide will select for resistance; a disease-resistant plant variety will select for pathogen strains able to evade its defences; even biocontrol by predatory insects can select for more effective hiding behaviours in the target prey.
With this universal principle in mind, scientists across the various disciplines are united in their warnings that there are no “silver bullets”, and durable control must use an integrated approach. This means that responding to resistance by abandoning chemical control in favour of the first available alternative would be counter-productive, as multiple control options are needed to reduce the pressure on any single component. Finding more alternative control measures is, of course, vital, but must be accompanied by research into how to make the best use of all available measures, combining different approaches and managing trade-offs between effective control now and avoiding selection for resistance in the future. The aim must be to develop durable control strategies, rather than just lining up a succession of individual novel control measures to fall like dominoes under the inevitable evolution of pests and pathogens.
In order to know how best to hold back resistance, we must better understand the evolutionary processes involved. In these more detailed questions too, there is much to be gained by drawing together research from across medical and plant health disciplines. For example, where do the resistance genes come from? Are they produced through new mutations, or were they out there at low levels all along? Can resistance risk against new drugs be predicted by screening the current population, or would we have to predict potential future mutations?
Some forms of antibiotic resistance are due to new mutations, but others originated long ago in response to natural antibiotics produced by competing microbes, and these resistance genes were then passed between bacterial species through horizontal gene transfer. Horizontal gene transfer can also occur in fungi, but doesn’t appear to be involved in any known cases of fungicide resistance: instead, the rapid, repeatable emergence of new mutations has happened independently in many different species. Resistance to the MBC fungicides has been reported in over 90 plant pathogens and QoI resistance has emerged multiple times even within species.
But how can we predict future resistance risk from mutations that haven’t happened yet? Here too, there are universal evolutionary ideas that can be applied to both human medicine and plant health. Experimental evolution can be used to see how populations adapt to a range of different scenarios, including selection by drugs or pesticides, and how repeatable the evolutionary outcomes are. At a more conceptual level, adaptive landscape models can provide reasons why some evolutionary pathways are more predictable than others. Evolutionary biologists have used antibiotic resistance in bacterial models in such studies and now we are using these ideas and methods for plant pathogens too. We have seen that the highest resistance-risk fungicides are those in which a small number of high resistance-factor mutations repeatedly evolve; in other cases, a wider range of mutations confer less resistance individually but can accumulate to cause high levels of resistance in the end.
By working together to apply these evolutionary concepts across human and plant health, the hope is that doctors and farmers alike can get a step ahead of the superbugs.
Feature image: False-colour SEM of Human Neutrophil – green – ingesting MRSA – purple – (left) and Fluorescence micrograph of Zymoseptoria tritici inside wheat mesophyll layer (right).