New Antibiotic Shows Promise against Gram-Positive Pathogen in Mice

Researchers at Washington University School of Medicine in St. Louis developed a novel compound that effectively clears Gram-positive bacterial infections in mice, in particular skin and soft tissue infections (SSTI) caused by Streptococcus pyogenes, an organism that can be associated with potentially fatal “flesh-eating” necrotizing fasciitis.

The compound, designated PS757, represents the first of an entirely new class of GmPcide (gram-positive-icide) antibiotics, and targets Gram-positive bacteria, which can cause drug-resistant staph infections, toxic shock syndrome, and other illnesses that may become deadly. The researchers suggest the compound could open up potential options for more effective treatments against bacteria that can’t easily be tackled using current antibiotics.

The reported studies were headed by scientists in the collaborating labs of Scott Hultgren, PhD, the Helen L. Stoever Professor of Molecular Microbiology, and Michael Caparon, PhD, a professor of molecular microbiology, together with Fredrik Almqvist, PhD, a professor of chemistry at the University of Umeå. Hultgren and Caparon are co-senior authors of the team’s published paper in Science Advances, titled “Dihydrothiazolo ring-fused 2-pyridone antimicrobial compounds treat Streptococcus pyogenes skin and soft tissue infection.”

Several factors, including the overuse and misuse of antibiotics, and exposure to environmental reservoirs of antibiotic-resistant bacteria, have contributed to rising rates of antibiotic resistance, the authors wrote. “The emergence of antibiotic resistance threatens health care and agriculture systems worldwide and raises the prospect of a post-antibiotic era.”

A new type of antimicrobial would be good news for clinicians seeking effective treatments against pathogens that are becoming more resistant to currently available drugs, and thus much more dangerous. “… there is an urgent need to develop new antibiotics that are recalcitrant to resistance development to combat multidrug-resistant pathogens,” the team continued.

The new antibiotic developed by Caparon, Hultgren, Almqvist, and colleagues is 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 an additional bonus.

The scientists have called the compound family, GmPcides. In previous work they showed that GmPcides can wipe out bacterial strains in petri dish experiments, and in their newly reported study the team tested one GmPcide compound against necrotizing soft tissue infections, which are fast-spreading infections usually involving 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.

For their study the team focused on Streptococcus pyogenes, a pathogen responsible for 500,000 deaths every year globally. “… we extensively characterized the therapeutic properties of GmPcide PS757 using well-characterized biofilm and murine SSTI models of S. pyogenes infection,” they wrote. Their studies confirmed that mice infected with S. pyogenes and treated with the GmPcide fared better than did untreated animals in almost every metric. They had less weight loss, ulcers characteristic of the infection were smaller, and the animals fought off the infection faster, the scientists noted. The compound appeared to reduce the virulence of the bacteria and, remarkably, led to faster post-infection healing of the damaged areas of the skin.

“Our results demonstrate that PS757 was effective against all stages of bacterial growth and biofilm formation in vitro and improved treatment outcomes in a murine SSTI model by decreasing bacterial burdens, reducing levels of tissue damage, attenuating inflammation, and accelerating the rate of wound healing,” they wrote. The results, they continued, “…  indicate that PS757 has antivirulence properties on streptococcal cells exposed to sublethal concentrations that may have contributed to its effective treatment of S. pyogenes SSTI in mice.”

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. “… the antimicrobial activity of GmPcide PS757 may be associated with targeting multiple pathways in S. pyogenes, including adverse membrane stress caused by inhibition of an essential pathway, including DNA replication, cell wall biosynthesis, or production of specific proteins,” they commented. Caparon added, “One of the jobs of a membrane is to exclude material from the outside. We know that within five to ten minutes of treatment with GmPcide, the membranes start to become permeable and allow things that normally should be excluded to enter into the bacteria, which suggests that those membranes have been damaged.”

This can disrupt the bacteria’s own functions, including those that cause damage to their host, and make the bacteria less effective at combating the host’s immune response to infections.

All of the gram-positive bacteria tested have been susceptible to the compound, Caparon added. “That includes enterococci, staphylococci, streptococci, C. difficile, which are the major pathogenic bacteria types. The compounds have broad-spectrum activity against numerous bacteria.”

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.

“In this study, we found that GmPcide PS757, a member of a novel family of antimicrobial compounds synthesized around a peptidomimetic ring-fused 2-pyridone scaffold, could prevent S. pyogenes biofilm formation and effectively treat S. pyogenes SSTI in a murine model,” the team stated. “Overall, these results demonstrate that GmPcides hold great promise in preventing and treating S. pyogenes SSTI … Our findings will help direct the continuing development and optimization of GmPcide compounds toward a novel class of antibiotics.”

Caparon acknowledged that there is a long way to go before GmPcides may find their way into 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 ownership stake. Their aim is to find a partner for potential commercial development of GmPcides.

Hultgren said that the kind of collaborative science that created GmPcides is what is needed to treat intractable problems like antimicrobial resistance. “Bacterial infections of every type are an important health problem, and they are increasingly becoming multi-drug resistant and thus harder to treat,” he said. “Interdisciplinary science facilitates the integration of different fields of study that can lead to synergistic new ideas that have the potential to help patients.”