A much-needed new kind of antibiotic can kill bacteria such as MRSA and works in a way that makes it extremely difficult for resistance to evolve.
A potential new antibiotic is highly effective against “superbugs” such as MRSA that are resistant to many existing antibiotics, and kills bacteria in an unusual way that means it will be extremely difficult for resistance to evolve.
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| An illustration of methicillin-resistant Staphylococcus aureus (MRSA) bacteria KATERYNA KON/SCIENCE PHOTO LIBRARY |
The antibiotic, clovibactin, was discovered in a rare bacterium isolated from sandy soil collected in North Carolina. Markus Weingarth at Utrecht University in the Netherlands and his colleagues have been studying how it works, with promising results. “The activity is even better than for the gold standard, vancomycin,” he says.
Antibiotic resistance is a major and growing problem around the world. It has been estimated that it killed 1.3 million people in 2019 – more than malaria and AIDS combined – and contributed to the deaths of almost another 4 million people.
This means there is a desperate need for new drugs that are capable of killing bacteria resistant to older antibiotics and, ideally, kill in new ways, so it is harder for resistance to evolve and spread.
Clovibactin fits the first criterion, as the team found it kills a range of disease-causing bacteria, including methicillin-resistant Staphylococcus aureus, better known as the MRSA superbug, and Mycobacterium tuberculosis, which causes TB. More importantly, Weingarth and his colleagues have also found that it works in a way unlike any other antibiotic.
Many existing antibiotics target the cell wall around bacteria, a rigid mesh-like structure surrounding the cell membrane. If this wall is disrupted, cells burst open and die. This is a good target because the wall isn’t found in animal cells, meaning the antibiotics kill only bacterial cells. But these existing antibiotics typically target the protein enzymes that assemble the cell wall, and bacteria can alter the shape of these enzymes to evade attack.
Clovibactin instead targets a chemical group called a pyrophosphate that is found on not just one, but three different building blocks of cell walls. So, to survive, a bacterium would have to alter all three building blocks. “The more targets you have, the more difficult it is for a bacteria to develop resistance,” says Weingarth. What’s more, any changes to these components would almost certainly stop the cell wall forming properly.
The team exposed bacteria to low doses of clovibactin to see if resistance emerged, but found none. “Although we tried very hard, there was no detectable resistance,” he says. Lower doses are more likely to lead to resistance because they expose bacteria to an antibiotic without killing them and any that acquire resistance will quickly out-compete others.
This doesn’t mean that resistance to clovibactin is impossible. For instance, many bacteria are classified as Gram-negative, meaning they have an extra membrane around the outside of the cell wall that protects them from some antibiotics, including clovibactin. Ones without this wall, Gram-positive, could in theory evolve a similar barrier to prevent clovibactin reaching their cell wall, but it is a major structural change that is very unlikely, says Weingarth.
“Clovibactin is a great lead for the development of a new class of antibiotics,” says Gerry Wright at McMaster University in Canada, who isn’t part of the team. “We have not approved a truly new anti-Gram-positive drug class for over 20 years.”
“While there is a lot of pressing concern about the need for new antibiotics that target Gram-negative bacteria, we have relatively few good alternative antibiotics for Gram-positive infections,” says Wright. “There is growing resistance to all available drugs and bacteria such as Staphylococcus aureus are among the most common sources of bacterial infections in and out of health care settings.”
In tests in mice, clovibactin didn’t appear to have any adverse effects, and it is now being developed further by a US-based company called NovoBiotic Pharmaceuticals. “It’s a very, very long way from mice to humans,” says Weingarth. “I don’t want to oversell this.”
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