How can we harness molecular mechanisms to combat AMR?

Researchers are contributing to our understanding of how resistance emerges at the level of cell wall manipulation.

Antibiotics saved millions of lives and helped radically lengthen life expectancy in the 20th century in developed and emerging economies. Surgery, organ transplants, giving birth, chemotherapy, hip replacements, and even small injuries, would often be fatal without these vital, under-appreciated pills. But their power is on the wane as bacteria adapt and evolve.

Respect the enemy: How medical researchers are learning from superbugs

Excessive and inappropriate use of antibiotics, in humans, livestock and agriculture, is creating the public health emergency of antimicrobial resistance: the ability of microorganisms, including bacteria but also viruses and parasites, to stop an antimicrobial from working, whether it be an antibiotic, an antiviral or an antimalarial1. The idea of drug-resistant diseases is rightly terrifying to health agencies - and a growing number of governments.

Official estimates suggest 700,000 people already die each year from drug-resistant disease. The real number is likely much higher given that cause-of-death data is often absent or inaccurate in poorer countries. Unchecked, the number of AMR fatalities could rise to 10 million a year by 2050. As well as the human cost, this poses a threat to public health systems given the financial impact of hospital admissions. Bacterial resistance levied a €290 million cost on French hospitals annually in 2015 and 2016, according to one estimate2.

Beating AMR means, in part, better ‘stewardship’: cutting down unnecessary use, improving education to ensure patients complete regimens, and restricting excessive use in the livestock and agriculture sectors. In Florida, even citrus trees are now sprayed with antibiotics3. But cutting usage alone will not be enough. We also need new insights to keep up with an innovative enemy. “Bacteria are masters of adaptation,” says Dr Andrew Lovering, senior lecturer in biosciences at the University of Birmingham. Knowing how resistance emerges in the first place is essential to disabling superbugs.   

How nature copes with resistance: The curious case of bacterial predators

Most resistant superbugs are ‘Gram-negative’, a term which describes their use of an outer membrane that shields them from antibiotics. Bypassing or compromising this outer membrane could help overcome their defence mechanism. It already happens in nature; there are bacterial predators which hunt and consume other bacteria. One of them, called Bdellovibrio bacteriovorus, burrows through the outer surface of bacteria and consumes them from within4. Andrew Lovering is researching such microorganisms to see how they penetrate this outer layer.

An image of bdellovibrio bacteriovorus - the predator bacteriaBdellovibrio bacteriovorus (Credit: Alfred Pasieka / Science photo Library)

Dr Patrick Moynihan, BBSRC David Phillips Fellow at the University of Birmingham, is also looking at the role of the cell wall. One of the defining features of almost all bacteria is a characteristic peptidoglycan cell wall, which wraps around the cell as a protective layer. The release of peptidoglycan during growth usually signals infection to the immune system, but pathogens can modify its release in ways that makes them resistant to the enzymes that ordinarily spot and fight infections.

Our bodies have “exquisite sensors to know when peptidoglycan is being released so they can mount a response,” says Moynihan. “Mycobacteria take those special molecules back into the cell to control the immune response in the host. If we can understand how they control peptidoglycan recycling, we can look at modulating the system so patients can better mount a response”.

Taking inspiration from nature

These approaches are part of ‘molecular microbiology’, which seeks to learn from nature. “We are more inspired by molecular mechanisms in use by nature than the chemical drug screening approach,” says Lovering.  “We are looking at basic mechanisms in biology, and asking: how can we harness those? What can they tell us about what we’re trying to kill? You can learn more about your enemy this way. You can then wedge the door open and tackle it more intelligently”. There is something to be gained by using millions of years of evolution to your advantage, in the same manner that the superbugs do.

Their approach sits within the broader field of ‘precision healthcare’ which, in part, tries to understand how natural defences are disabled by diseases. In cancer, for instance, immunotherapy research is looking to reinvigorate the body’s compromised immune response. These approaches are warranted because, despite the marvels of modern science, we are often in essence just carpet-bombing diseases, whether through chemotherapy or antibiotics. This very process could even worsen the problem in the long run. “Clostridium difficile came about because you are wiping too many cells out - it becomes a problem because you’ve got rid of natural bacteria too. A more targeted approach, backed by fundamental biology, is a better way” says Lovering.

Lovering and Moynihan agree that there is no single approach to AMR, partly because AMR is not one phenomenon. “You are looking at organisms as alike as pigs and elephants,” says Moynihan. “The evolutionary distance between AMR organisms is truly massive, so it’s a completely different question how to combat those. You might be working on an element of AMR in E. coli or TB and they are not necessarily going to be related in an easily identifiable way”. 

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If international researchers can peel off different pieces of the puzzle, the resulting findings will more likely lead to breakthroughs. “There are many labs doing basic biology research on organisms. From that breadth and volume of understanding, a few really good things will come out,” says Lovering. But this requires basic science funding and engagement from academia, since the pharmaceutical industry, despite being the manufacturer of our antibiotics to date, is investing little in AMR.  This is hardly surprising given the low prices of antibiotics and the new ethos of reduced usage.

Science funders need to back diverse approaches, says Moynihan. “Much of modern molecular medicine is based on polymerase chain reaction (PCRs) and enzymes, which we discovered because someone decided to hang glass slides in hot springs in Yellowstone National Park,” he says. “Trying to pitch that as a grant today would be impossible but much of modern science is built on that experiment. It is of paramount importance that funding covers as broad a range of ideas as possible so we can catch those serendipitous results and outcomes”.

Pencil graphic of an enzyme

An enzyme Bdellovibrio uses to manipulate the wall of prey

Strong public funding is warranted given how the problem will worsen, not just through the natural growth in bacterial resistance over time, but also due to how dynamics like climate change could increase the spread of diseases and enable new ones to emerge. “As the environment warms, species that have been present, but not as pathogens, will learn to cope with increased temperatures, which will then allow them to persist in the body. Us being warm blooded may have prevented them being pathogens so far,” says Lovering.

Climate change and extreme weather could also impact migration, as people flee hot areas, or escape weather-related disaster. This could accelerate the spread of infectious diseases as a whole. “Changes in weather will alter how people migrate,” says Patrick Moynihan. “For TB, where close human contact is important, the disease will spread in places where migration increases”.

In that context, research funding must support diverse approaches to fighting bacterial resistance, and nurture the positive results the science community is now realising in the lab.

Notes:

  1. https://www.who.int/antimicrobial-resistance/en/
  2. https://www.pasteur.fr/en/home/press-area/press-documents/overall-annual-cost-infections-due-bacterial-resistance-french-hospitals-now-estimated-290-million
  3. https://www.nature.com/articles/d41586-019-00878-4
  4. https://wellcome.ac.uk/funding/people-and-projects/grants-awarded/combating-gramnegative-amr-pathogens-by-understanding

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