Researchers at Washington University School of Medicine in St. Louis have developed a new drug that effectively clears bacterial infections in mice, including infections that can lead to rare but potentially fatal “flesh-eating” diseases. The drug could be the first of a whole new class of antibiotics, and a gift to doctors looking for more effective treatments against bacteria that are not easily tamed with current antibiotics.
The research will be published on August 2 Scientific progress.
The compound targets gram-positive bacteria, which can cause resistant staph infections, toxic shock syndrome and other diseases that can be fatal. It was developed through a collaboration between the laboratories of Scott Hultgren, PhD, the Helen L. Stoever Professor of Molecular Microbiology, and Michael Caparon, PhD, a professor of molecular microbiology, and Fredrik Almqvist, a professor of chemistry at the University of Umeå. in Sweden.
A new type of antimicrobial agent would be good news for doctors looking for effective treatments against pathogens that are becoming more resistant to currently available drugs and therefore much more dangerous.
“All of the gram-positive bacteria we tested are sensitive to that compound. That includes enterococci, staphylococci, streptococci, C. difficultwhich are the major pathogenic bacterial types,” says Caparon, the co-senior author. “The compounds have broad-spectrum activity against numerous bacteria.”
It is based on a type of molecule called ring-fused 2-pyridone. Initially, Caparon and Hultgren had asked Almqvist to develop a compound that could prevent bacterial films from adhering to the surface of urethral catheters, a common cause of hospital-associated urinary tract infections. The discovery that the resulting compound had infection-fighting properties against multiple types of bacteria was a fortunate coincidence.
The team named their new family of compounds GmPcides (for gram-positive icide). In previous work, the authors have shown that GmPcides can eradicate bacterial strains in Petri dish experiments. In this latest study, they decided to test it for necrotizing soft tissue infections, which are fast-spreading infections that usually involve multiple types of gram-positive bacteria, for which Caparon already had a working mouse model. The best known of these, necrotizing fasciitis or “flesh-eating disease,” can quickly damage tissue severely enough to require limb amputation to control its spread. About 20% of patients with flesh-eating disease die.
This study focused on one pathogen, Streptococcus pyogenes, which is responsible for 500,000 deaths worldwide every year, including flesh-eating diseases. Mice infected with S. pyogenes and treated with a GmPcide performed better than untreated animals in almost all metrics. They had less weight loss, the sores characteristic of the infection were smaller and they fought the infection more quickly.
The compound appeared to reduce the virulence of the bacteria and, remarkably, speed up the healing of the damaged areas of the skin after infection.
It’s not clear how GmPcides accomplishes all this, but microscopic examination shows that the treatment appears to have a significant effect on bacterial cell membranes, which form the outer covering of the microbes.
“One of the jobs of a membrane is to keep outside material out,” Caparon said. “We know that within five to 10 minutes of treatment with GmPcide, the membranes become permeable and allow things that would normally be excluded to enter the bacteria, indicating that those membranes are damaged.”
This can disrupt the bacteria’s own functions, including those that cause damage to the host, and make the bacteria less effective at fighting the host’s immune response to infections.
In addition to their antibacterial effectiveness, GmPcides appear less likely to lead to drug-resistant strains. Experiments designed to create resistant bacteria found that very few cells could withstand the treatment and thus pass on their benefits to the next generation of bacteria.
Caparon explained that there is still a long way to go before GmPcides are likely to find their way into local pharmacies. Caparon, Hultgren and Almqvist have patented and licensed the compound used in the study to a company, QureTech Bio, in which they have an ownership interest, in the expectation that they will be able to collaborate with a company that has the capacity to develop the pharmaceutical development and clinical trials to potentially commercialize GmPcides.
Hultgren said the kind of collaborative science that GmPcides has created is needed to treat persistent problems such as antimicrobial resistance.
“Bacterial infections of all types are a major health problem, and they are becoming increasingly resistant to multiple drugs and therefore more difficult to treat,” he said. “Interdisciplinary science facilitates the integration of different fields, which can lead to synergistic new ideas that have the potential to help patients.”
