Targeting Gram-Positive Bacteria
The newly developed compound specifically targets gram-positive bacteria, which are known for causing drug-resistant staph infections, toxic shock syndrome, and other severe illnesses. This research is the result of a collaborative effort involving Dr. Scott Hultgren, the Helen L. Stoever Professor of Molecular Microbiology, Dr. Michael Caparon, a professor of molecular microbiology, and Dr. Fredrik Almqvist, a professor of chemistry at the University of Umeå in Sweden.
Dr. Caparon, co-senior author of the study, stated, “All of the gram-positive bacteria we’ve tested have been susceptible to this compound, including enterococci, staphylococci, streptococci, and C. difficile, which are major pathogenic bacteria.”
Development of GmPcides
The compound is based on a molecule known as ring-fused 2-pyridone. Initially, Drs. Caparon and Hultgren tasked Dr. Almqvist with creating a compound to prevent bacterial biofilms from adhering to urethral catheters, a common source of hospital-acquired urinary tract infections. The discovery that this compound also possesses infection-fighting properties across multiple bacterial types was an unexpected but welcome outcome.
The research team has named this new class of compounds "GmPcides," short for gram-positive-icide. Previous studies have shown that GmPcides can effectively eliminate bacterial strains in laboratory settings. In this latest investigation, the focus was on necrotizing soft-tissue infections, which are rapidly spreading infections typically involving various gram-positive bacteria. Dr. Caparon had established a mouse model for these infections, including necrotizing fasciitis, commonly referred to as "flesh-eating disease," which can cause severe tissue damage and may necessitate limb amputation. Approximately 20% of patients afflicted with this condition do not survive.
Efficacy Against Streptococcus pyogenes
The study specifically examined Streptococcus pyogenes, a pathogen responsible for an estimated 500,000 deaths annually worldwide, including cases of flesh-eating disease. Mice infected with S. pyogenes and treated with GmPcide showed significantly better outcomes compared to untreated counterparts, exhibiting less weight loss, smaller ulcers, and a more rapid recovery from infection.
Remarkably, the compound appeared to reduce the virulence of the bacteria and accelerate the healing process of damaged skin areas. While the precise mechanisms by which GmPcides operate remain unclear, microscopic analyses indicated that the treatment significantly impacts bacterial cell membranes, which serve as the outer barrier of the microbes.
Dr. Caparon explained, “One of the roles of a membrane is to exclude external materials. We observed that within five to ten minutes of GmPcide treatment, the membranes began to lose their integrity, allowing substances that should normally be excluded to enter the bacteria, suggesting membrane damage.”
This disruption can impair the bacteria's functions, including those that facilitate damage to their host, thereby enhancing the host's immune response against infections.
Lower Risk of Drug Resistance
In addition to their antibacterial properties, GmPcides appear to have a lower likelihood of fostering drug-resistant bacterial strains. Experiments aimed at inducing resistance yielded very few cells capable of surviving treatment, minimizing the potential for these traits to be passed on to subsequent generations of bacteria.
Future Steps for GmPcides
Despite these promising results, Dr. Caparon cautioned that significant work remains before GmPcides can be made available in pharmacies. The researchers have patented the compound and licensed it to QureTech Bio, a company in which they hold an ownership stake. They anticipate collaborating with a pharmaceutical firm capable of managing the necessary development and clinical trials to bring GmPcides to market.
The Importance of Collaborative Science
Dr. Hultgren emphasized the importance of collaborative science in addressing complex issues like antimicrobial resistance. “Bacterial infections of all types pose a significant health challenge, increasingly becoming multidrug resistant and more difficult to treat. Interdisciplinary research fosters the integration of diverse fields, leading to innovative ideas that have the potential to benefit patients,” he stated.
