Streptococcus Pyrogenese bound To human neutrophil. Credit: NIH
A new study published in Nature Communications reveals a novel approach to mitigating tissue damage caused by Streptococcus pyogenes, the flesh-eating bacterium responsible for severe infections such as necrotising fasciitis. The research highlights how disrupting bacterial metabolism can help the body better tolerate infection and heal more effectively.
The study was led by Wei Xu, PhD, an assistant professor of biomedical sciences at the Marshall University Joan C. Edwards School of Medicine, and colleagues at Washington University School of Medicine and Central China Normal University. The team discovered that S. pyogenes manipulates the body’s immune response through its aerobic mixed-acid fermentation process, which produces metabolic byproducts, such as acetate and formate, that impair immune cell function, delay bacterial clearance and slow wound healing.
By inhibiting this bacterial metabolic pathway with a pyruvate dehydrogenase inhibitor, the team successfully reduced tissue damage in a mouse model of necrotising skin infection. These findings suggest that reprogramming bacterial metabolism could serve as a novel therapeutic approach, not only to improve host tolerance but also as a potential adjuvant therapy alongside antibiotics. This strategy could enhance the effectiveness of existing treatments, particularly in severe infections where antibiotic resistance or excessive inflammation worsens patient outcomes.
“This study sheds light on how bacterial metabolism influences the immune system,” Xu said. “By understanding these interactions, we can develop new treatment strategies that protect tissues, enhance antibiotic efficacy and improve patient outcomes.”
More than 100 000 people die from snake bites every year. Cobra antivenom is expensive and doesn’t treat the necrosis of flesh caused by the bite, which can lead to amputations. Now, Scientists at the University of Sydney and Liverpool School of Tropical Medicine have made a remarkable discovery: a commonly used blood thinner, heparin, can be repurposed as an inexpensive antidote for cobra venom.
“Our discovery could drastically reduce the terrible injuries from necrosis caused by cobra bites – and it might also slow the venom, which could improve survival rates,” said Professor Greg Neely, a corresponding author of the study from the University of Sydney.
Using CRISPR gene-editing technology to identify ways to block cobra venom, the team, which consisted of scientists based in Australia, Canada, Costa Rica and the UK, successfully repurposed heparin and related drugs and showed they can stop the necrosis caused by cobra bites.
PhD student and lead author, Tian Du, also from the University of Sydney, said: “Heparin is inexpensive, ubiquitous and a World Health Organization-listed Essential Medicine. After successful human trials, it could be rolled out relatively quickly to become a cheap, safe and effective drug for treating cobra bites.”
The team used CRISPR to find the human genes that cobra venom needs to cause necrosis that kills the flesh around the bite. One of the required venom targets are enzymes needed to produce the related molecules heparan and heparin, which many human and animal cells produce. Heparan is on the cell surface and heparin is released during an immune response. Their similar structure means the venom can bind to both. The team used this knowledge to make an antidote that can stop necrosis in human cells and mice.
Unlike current antivenoms for cobra bites, which are 19th century technologies, the heparinoid drugs act as a ‘decoy’ antidote. By flooding the bite site with ‘decoy’ heparin sulfate or related heparinoid molecules, the antidote can bind to and neutralise the toxins within the venom that cause tissue damage.
Joint corresponding author, Professor Nicholas Casewell, Head of the Centre for Snakebite Research & Interventions at Liverpool School of Tropical Medicine, said: “Snakebites remain the deadliest of the neglected tropical diseases, with its burden landing overwhelmingly on rural communities in low- and middle-income countries.
“Our findings are exciting because current antivenoms are largely ineffective against severe local envenoming, which involves painful progressive swelling, blistering and/or tissue necrosis around the bite site. This can lead to loss of limb function, amputation and lifelong disability.”
Snakebites kill up to 138 000 people a year, with 400 000 more experiencing long-term consequences of the bite. While the number affected by cobras is unclear, in some parts of India and Africa, cobra species account for most snakebite incidents.
Working in the Dr John and Anne Chong Laboratory for Functional Genomics at the Charles Perkins Centre, Professor Neely’s team takes a systematic approach to finding drugs to treat deadly or painful venoms. It does this using CRISPR to identify the genetic targets used by a venom or toxin inside humans and other mammals. It then uses this knowledge to design ways to block this interaction and ideally protect people from the deadly actions of these venoms.
