Aim: New antibiotics with modes of action different from currently registered drug classes are urgently needed to combat the increasing global spread of multidrug-resistant pathogens.
Background: Animal models for detailed preclinical investigation of disease progression that closely mimic infection in humans and animals are arduous, expensive and often involve the use of separate animal cohorts at each stage of the disease process.
Methods: We have optimised bioluminescent peritonitis-sepsis models of bacteraemia in mice by infection with recombinant luciferase-expressing Staphylococcus aureus (Xen29) and Escherichia coli (Xen14). We have used these refined models to examine the efficacy of the first-generation 2-aminopyramidine robenidine analogue NCL195 (-/+ low dose colistin) against S. aureus or E. coli infection compared to moxifloxacin or high dose colistin in bioluminescent peritonitis-sepsis models.
Results: In the S. aureus infection model, oral treatment of mice with NCL195 resulted in significantly reduced S. aureus infection loads (p<0.01) and longer survival times (p<0.001) than vehicle-only treated mice. In the E. coli infection model, co-administration of NCL195 and graded doses of colistin resulted in a dose-dependent significant reduction in colistin-susceptible (p<0.01) or colistin-resistant (p<0.05) E. coli loads compared to treatment with colistin alone at similar concentrations.
Conclusions: The bioluminescent models can replace conventional quantitative culture and for preclinical efficacy testing of new drug classes for treating bacterial infections. NCL195 is a potential candidate for further preclinical development as a specific treatment for multidrug-resistant infections either as a stand-alone antibiotic for Gram-positive bacteria or in combination with sub-inhibitory concentrations of colistin for Gram-negative bacteria.