![]() Efficacy in mouse modelsĪfter establishing an effective dose of fabimycin in mice, the researchers evaluated the efficacy of fabimycin in mice infected with a challenging, drug-resistant strain of Escherichia coli. This discovery suggests that fabimycin could be less damaging to gut microflora than typical broad-spectrum antibiotics. The researchers attribute this to the fact that commensal bacteria may not be reliant on the FabI enzyme and would thus be insensitive to FabI enzyme inhibition by fabimycin. This result encouraged the authors “because it suggests that intrinsic resistance to fabimycin is not prevalent in existing bacterial populations.”įurthermore, fabimycin demonstrated high specificity for pathogenic versus commensal bacteria (normal microflora). Out of a suite of newly-synthesized Debio-1452 drug candidates, one molecule - which the researchers coined fabimycin - showed superior potency in initial tests. Guided by the eNTRy rules, the researchers made structural modifications to the Debio-1452 molecule with the objective of creating a new molecule that retained the FabI inhibition potency of Debio-1452 but also possessed activity against Gram-negative bacteria. Hergenrother’s team started with Debio-1452, a FabI inhibitor highly potent against Gram-positive Staphylococcus aureus. This emerging knowledge is captured in new guidelines for the design of Gram-negative penetrant compounds, known as the. ![]() Researchers have come to understand that the physicochemical traits of small molecules impact their ability to penetrate and accumulate inside Gram-negative bacterial cells. The results of this study appear in ACS Central Science. Before this study, the use of the FabI enzyme as an antibiotic target had only been leveraged in Gram-positive infections. Hergenrother and his team decided to target the FabI enzyme, which is responsible for catalyzing the rate-determining step in bacterial fatty acid biosynthesis. A majority of the pathogens listed by the WHO are Gram-negative bacteria.ĭr. In 2017, the World Health Organization (WHO) identified a list of antibiotic-resistant priority pathogens that present a “great threat to human health.” The agency highlighted the urgency of the need for new antibiotics. In comparison, Gram-positive bacteria lack the outer layer, but are surrounded by thick layers of the mesh-like peptidoglycan.ĭue to the cell structural difference, Gram-negative bacteria, such as pneumonia, urinary tract infections (UTI), and bloodstream infections, are harder to treat compared to those caused by Gram-positive bacteria. These bacteria were categorized as Gram-negative, and their cell structure prevents antibiotic molecules from entering and accumulating within the cell. Gram found that some bacteria had a thin peptidoglycan cell wall, in addition to a dense outer membrane and efflux pumps. In 1884, a Danish bacteriologist named Hans Christian Gram developed a test to differentiate bacteria based on the chemical and physical makeup of their cell walls. Findings suggest that fabimycin could eventually be used to treat Gram-negative infections in humans.īacterial antimicrobial resistance (AMR) occurs when bacteria mutate over time and no longer respond to antibiotics, making infections more difficult to treat and increasing the risk of disease spread, severe illness, and death. Scientists have described infections due to antibiotic-resistant bacteria as a threat to modern healthcare.īacteria can be categorized as Gram-positive or Gram-negative based on the structure of their cell membranes.Fabimycin also showed efficacy against Gram-negative bacteria in mouse infection models of a challenging urinary tract infection (UTI) and acute pneumonia.One molecule synthesized by the researchers, fabimycin, showed promise in combating more than 200 Gram-negative bacteria and didn’t have a significant impact on the harmless bacteria that are typically present in the human gut microbiome.Researchers modified an existing antibiotic to create a new molecule that may be effective against Gram-negative bacteria that are drug resistant.Share on Pinterest WLADIMIR BULGAR/Getty Images
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