Nanoparticles Combining Host-Directed Therapeutics and Antibiotics to Boost Bacterial Killing and Overall Survival of Zebrafish Embryos Infected with Mycobacterium Marinum

Abstract

The bacterial pathogen, Mycobacterium tuberculosis (Mtb), remains a leading cause of global morbidity and mortality. Due to the complexity of the infection, the limited efficacy of antibiotics, and the increasing incidence of multi-drug resistant strains, novel therapeutics are urgently needed. An interesting new approach is to combine antibiotics with treatments that boost the natural ability of host cells to kill the bacteria, so-called host-directed therapeutics (HDT). Until now, this approach has not been explored in the context of nanoparticle drug delivery, which may offer several advantages. Here, the HDT drug everolimus and the antibiotic ((S)-2-nitro-6-((5-((4-(trifluoromethoxy)phenyl)ethynyl)pyridin-2-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine, drug D) are focused on. Both of these agents, drug D and everolimus, are encapsulated into one single micelle (PeptoMicelles), resulting in formulation C, and compared with micelles containing only drug D (formulation A) or everolimus (formulation B). They are tested in Mtb-infected primary macrophages and THP-1 cells, and in the zebrafish model for TB (Mm infection) using embryo survival analysis. The results show that formulation C, containing drug D and everolimus in one micelle, is significantly more efficient in protecting cells and zebrafish embryos against infection than all other formulations, indicating an improved therapeutic efficacy of HDTs and antibiotics in a single polymeric micelle.