Researchers at Washington University School of Medicine in St. Louis have developed a new compound that effectively kills bacterial infections in mice, including those that can lead to rare but potentially deadly “flesh-eating” diseases. The compound could be the first in an entirely new class of antibiotics and a boon to doctors seeking more effective treatments against bacteria that can’t be easily controlled with current antibiotics.
The research is published on August 2 in Scientific advances.
The compound targets gram-positive bacteria, which can cause drug-resistant staph infections, toxic shock syndrome and other life-threatening illnesses. 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, Professor of Molecular Microbiology, and Fredrik Almqvist, Professor of Chemistry at Umeå University in Sweden.
A new type of antimicrobial would be welcome news for doctors seeking effective treatments against pathogens that are becoming more resistant to currently available drugs and therefore much more dangerous.
“All the gram-positive bacteria we’ve tested have been susceptible to that compound. That includes enterococci, staphylococci, streptococci, C. difficile“The compounds have broad-spectrum activity against numerous bacteria,” said Caparon, co-lead author of the study.
It is based on a type of molecule called ring-fused 2-pyridone. Caparon and Hultgren had initially asked Almqvist to develop a compound that could prevent bacterial films from sticking 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-icide). In previous work, the authors showed that GmPcides can kill bacterial strains in petri dish experiments. In this latest study, they decided to test it on necrotizing soft tissue infections, which are fast-spreading infections that typically 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 rapidly damage tissue severely enough to require amputation of a limb to control its spread. About 20% of patients with the flesh-eating disease die.
This study focused on one pathogen, Streptococcus pyogeneswhich is responsible for 500,000 deaths each year worldwide, including flesh-eating disease. Mice infected with S. pyogenes Animals treated with a GmPcide fared better than untreated animals on almost every parameter: they lost less weight, the ulcers characteristic of the infection were smaller, and they fought off the infection more quickly.
The compound appeared to reduce the virulence of the bacteria and, notably, accelerate the healing of damaged skin areas after infection.
It’s unclear how the GmPcides accomplish all this, but microscopic examination revealed that the treatment appears to have a significant effect on bacterial cell membranes, which are the outer envelope of microbes.
“One of the functions of a membrane is to exclude material from the outside,” Caparon said. “We know that within five to 10 minutes of treatment with GmPcide, membranes begin to become permeable and allow things that should normally be excluded to enter the bacteria, suggesting that those membranes have been damaged.”
This can disrupt the bacteria’s own functions, including those that cause harm to their host, and make the bacteria less effective at fighting the host’s immune response to infections.
In addition to their antibacterial efficacy, GmPcides appear to be less likely to generate drug-resistant strains. Experiments designed to create resistant bacteria found that very few cells were able to withstand the treatment and thus pass on their advantages to the next generation of bacteria.
Caparon explained that there is still a long way to go before GmPcides can reach local pharmacies. Caparon, Hultgren and Almqvist have patented the compound used in the study and licensed it to a company, QureTech Bio, in which they have an equity stake, with the expectation of being able to collaborate with a company that has the capacity to manage pharmaceutical development and clinical trials to potentially bring GmPcides to market.
Hultgren said the kind of collaborative science that created GmPcides is what is needed to address intractable problems like antimicrobial resistance.
“Bacterial infections of all kinds are a major health problem and are increasingly multi-drug resistant and therefore more difficult to treat,” he said. “Interdisciplinary science facilitates the integration of different fields of study that can lead to new synergistic insights that have the potential to help patients.”