Gram-positively fuming: new drug candidate fights back against flesh-eating bacteria
In a recent study, researchers demonstrated that a novel compound could treat flesh-eating Gram-positive bacterial infections in mice, potentially offering a new class of antibiotics.
Researchers at Washington University of Medicine in St. Louis (MO, USA) have tested the efficacy of a compound in the GmPcide family – a novel set of compounds targeting Gram-positive bacteria – on necrotizing soft-tissue infections in mice. The findings have important implications for antibiotic development, potentially offering a new class of antibiotics that are more robust than existing antibiotics against Gram-positive bacterial infections.
In 2021, as part of a funding initiative to find new ways to combat the global threat of antibiotic resistance, a collaboration between Washington University and the University of Umeå (Sweden) developed GmPcides. GmPcides are a novel family of ring-fused 2-pyridone compounds that are bactericidal against a broad spectrum of Gram-positive species, both when administered alone and in conjunction with other antibiotics, as they boost the bacteria-killing effects of other antibiotics.
In the previous study, they demonstrated the compounds’ efficacy against a range of bacteria – including Streptococcus pyogenes – in petri dish experiments. Now, they are turning their attention to necrotizing fasciitis, a fast-spreading infection often involving multiple Gram-positive bacteria; focusing on one pathogen previously tested and known to be involved in necrotizing fasciitis, S. pyogenes. The researchers had already determined the minimum inhibitory concentrations of their GmPcides for certain Gram-positive bacteria, which had highlighted GmPcide PS757 as a potential candidate for treating S. pyogenes. The present study confirmed the potency of the candidate against S. pyogenes by determining its minimum bactericidal concentration against the bacteria.
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Testing PS757 in both mouse and biofilm models, they found that it was effective against bacterial growth and biofilm formation in vitro and in mice, reducing tissue damage and accelerating wound healing. Using transmission electron microscopy, the researchers examined the PS757-treated bacterial cells, finding extensive nucleoid abnormalities. Additionally, cell staining revealed that PS757-treated bacteria exhibited irregular membrane structures.
“One of the jobs of a membrane is to exclude material from the outside,” explained senior author Michael Caparon (Washington Univeristy). “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.”
By targeting the membrane, bacterial function is compromised, making it less effective at fighting off the host’s immune system and more permeable to other antibiotics if administered together. In addition to GmPcide PS757’s antibacterial efficacy, it has also been found less likely to lead to drug-resistant strains; in studies that aimed to create resistant bacteria, it was observed that very few cells survive GmPcide treatment and therefore cannot pass on resistance to the next generation.
Having developed GmPcides further since their initial creation, the researchers hope to take this potential new class of antibiotics to clinical trials soon, especially following this study, which demonstrated the considerable promise of GmPcides for treating S. pyogenes infections.