Targeting wild-type and drug-resistant mycobacteria in infected macrophages using drug-coated nanoparticles

BACKGROUND Tuberculosis therapeutics is facing a crisis because of the emergence of new multi and total drug-resistant strains of Mycobacterium tuberculosis. Increasing intra-bacterial as well as intra-macrophage drug concentrations through nanoparticles is a promising approach to target resistant bacteria. RESULTS To target both wild-type (WT) and resistant Mycobacterium smegmatis (NORr), positively-charged norfloxacin-coated iron oxide nanoparticles (NOR@IONP) were synthesized. While these particles are taken up identically in both WT and NORr, drug uptake was up to 4-fold higher in cells treated with NOR@IONP compared with the corresponding free drug. This increased intracellular drug accumulation also translated to an enhanced rate of bacterial killing, as is observed in the kill kinetics study. The coated nanoparticles also proved to be effective in reducing the minimum inhibitory concentration (MIC) of NOR towards Mycobacterium bovis BCG strain. Further, the effectiveness of NOR@IONP was also studied against differentiated THP1 cells infected with WT or NORr M. smegmatis. Intracellular bacterial clearance studies indicated that the NOR concentration required to kill intracellular WT or drug-resistant bacteria is 2-fold lower when treated with NOR@IONP. CONCLUSION This antibiotic-coated nanoparticle formulation is a novel antimicrobial agent with the potential to target both WT and resistant strains of mycobacteria present intracellularly. (c) 2018 Society of Chemical Industr