Identification of a Novel non-antibiotic Bactericidal agent to fight antimicrobial resistance
To stem the ever-growing threat of antimicrobial resistance (AMR) our research focuses on non-antibiotic strategies to combat multi-drug resistant (MDR) pathogens. We have developed up to the preclinical stage an inhibitor, 3A11, which is the first targeting copper-transporting P-type ATPase protein CopA. It limits the growth of several Gram-positive pathogens, such as Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, including the two most common MDR strains causing nosocomial infections: methicillin-resistant S. aureus and vancomycin-resistant enterococci. We will collect sequenced clinical isolates from the vast bacterial repositories of the project partners to test the bactericidal potential of 3A11. The inclusion of clinical isolates with different phenotypes and genetic lineages will guide our investigations of the underlying molecular mechanisms of action. This will be further studied using transcriptomic analysis to determine changes in the global expression profiles of the isolates induced by 3A11. As part of the preclinical development, we will investigate the potential development of resistance to 3A11 by determining the mutation rates in the bacteria and further characterising the ensuing phenotypes, genotypes, and fitness cost. Lastly, as bacterial pathogenesis initiates in epithelial cells within the host, followed by bacterial uptake in macrophages, we will gauge the efficacy of 3A11 in epithelial cells like human keratinocytes (HaCaT), primary keratinocytes, human macrophage cells (THP-1), and in murine models.
- Shilpa Ray, Karolinska Institutet, Sweden (Coordinator)
- Vincent CATTOIR, Université de Rennes, France (Partner)
- Gerard Lina, Centre International de Recherche en Infectiologie, France (Partner)
- Anne Santerre Henriksen, Maxel Consulting ApS, Denmark (Partner)
- Anders Rhod Larsen, Statens Serum Institute, Denmark (Partner)
The massive scope of antimicrobial resistance (AMR) has prompted scientists to investigate alternatives to antibiotics for the treatment of patients afflicted by multidrug-resistant (MDR) bacteria. We have designed a unique inhibitor of the copper P-type ATPase, 3A11 and developed it to its preclinical phase. We have shown it to be effective against several major Gram-positive pathogens, including MDR bacteria such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus (VRE). This is of great importance, due to the current lack of treatment options for VRE. To test the efficacy of our inhibitor, 3A11, against a plethora of strains, a vast panel of clinical isolates from the repositories of the project partners will be employed. The antimicrobial effects of 3A11 against this panel will be assessed and investigated in vitro to better understand the underlying molecular mechanisms of action. Additionally, to have a better model of the interactions between 3A11 and host cells, the bactericidal effects of this inhibitor will be analyzed both in human cells and in mice. A better understanding of the effects of 3A11 on bacterial cells and its molecular mechanisms of action will assess the suitability of this inhibitor as a non-antibiotic agent in the fight against AMR.