NEWS Researchers at Umeå University and Washington University School of Medicine in St. Louis have developed a novel compound that effectively clears bacterial infections in mice, including those that can result in rare but potentially fatal “flesh-eating” illnesses.
Researchers have developed a potential drug that is effective against common bacteria that can lead to rare, dangerous illnesses. Shown on the left are untreated Streptococcus pyogenes bacteria. After treatment with the compound, the dish is full of dead bacteria (image on right).
ImageZongsen Zou, Washington University School of Medicine in St. LouisThe research was recently published in the scientific journal Science Advances.
The potential drug, now tested for the first time in mice, could be the first of an entirely new class of antibiotics against hard-to-fight bacteria. The compound targets gram-positive bacteria, which can cause drug-resistant staph infections, toxic shock syndrome and other illnesses that can turn deadly. It was developed through a collaboration between the Washington University labs of Scott Hultgren and Michael Caparon, and Fredrik Almqvist, a professor in organic chemistry at Umeå University.
“All of the gram-positive bacteria that we’ve tested have been susceptible to that compound. That includes enterococci, staphylococci, streptococci, C. difficile, which are the major pathogenic bacteria types. The compounds have broad-spectrum activity against numerous bacteria,” says Michael Caparon, the co-senior author.
It’s based on a type of molecule called ring-fused 2-pyridone. Initially, Caparon and Hultgren had asked Almqvist to develop a compound that might prevent bacterial films from attaching to the surface of urethral catheters, a common cause of hospital-associated urinary tract infections. Discovering that the resulting compound had infection-fighting properties against multiple types of bacteria was a happy accident.
The team named their new family of compounds GmPcides (for gram-positive-cide). In past work, the authors showed that GmPcides can wipe out bacteria strains in petri dish experiments. In this latest study, they decided to test it on necrotizing soft-tissue infections.
This study focused on one pathogen, Streptococcus pyogenes, which is responsible for 500,000 deaths every year globally, including flesh-eating disease. Mice infected with S. pyogenes and treated with a GmPcide fared better than did untreated animals in almost every metric. They had less weight loss, the ulcers characteristic of the infection were smaller, and they fought off the infection faster.
The compound appeared to reduce the virulence of the bacteria and, remarkably, speed up postinfection healing of the damaged areas of the skin. It is not clear how GmPcides accomplish all of this, but microscopic examination revealed that the treatment appears to have a significant effect on bacterial cell membranes, which are the outer wrapping of the microbes.
In addition to their antibacterial effectiveness, GmPcides appear to be less likely to lead to drug-resistant strains. Experiments designed to create resistant bacteria found very few cells able to withstand treatment and thus pass on their advantages to the next generation of bacteria.
Caparon explains that there is a long way to go before GmPcides are likely to find their way into local pharmacies. Caparon, Hultgren and Almqvist have patented the compound used in the study and licensed it to a company, in which they have an ownership stake, with the expectation that they will be able to collaborate with a company that has the capacity to manage the pharmaceutical development and clinical trials to potentially bring GmPcides to market.
Zou Z, Singh P, Pinkner J, Obernuefemann CLP, Xu W, Nye TM, Dodson KW, Almqvist F, Hultgren SJ, Caparon MG. Dihydrothiazolo ring-fused 2-pyridone antimicrobial compounds treat Streptococcus pyogenes skin and soft tissue infection. Science Advances. Aug. 2, 2024. DOI: 10.1101/2024.01.02.573960
