Capuramycin (CM) antibiotics are bactericidal for Mycobacterium tuberculosis (MTB) in vitro. Due to their low membrane permeability and efflux, however, these compounds are less effective against intracellular MTB. To improve intracellular activity, we created phospholipid Phosal 53 MCT-based nanoemulsion (NE) formulations of CM analogues SQ641, SQ641-aua, SQ641-2aua and SQ997-3aua. We assessed intracellular killing activity of the 4 CM analogues and their NE formulations against MTB using the J774A.1 mouse macrophage cell line. Of the several emulsifiers investigated, d-tocopheryl polyethylene glycol 1000 succinate (TPGS) produced the most efficacious and stable emulsion, with a mean particle size below 70 nm. CM analogue-NE formulations prepared using TPGS as emulsifier (-NETPGS) showed significantly improved intracellular activity over free drugs. The order of intracellular activity was SQ641-2aua- NETPGS > SQ997-3aua-NETPGS > SQ641-aua-NETPGS > SQ641-NETPGS. At 2× MIC the intracellular killing activity of SQ641- 2aua-NETPGS, the most active formulation, surpassed that of first-line anti-TB drugs isoniazid (INH), rifampin (RIF) and ethambutol (EMB). Enhanced intracellular activity of the -NETPGS formulation, perhaps, was due to TPGS mediated blocking of the drug efflux.
Keywords: Anti-TB drugs, SQ641, phospholipids, nanoemulsion, M.tuberculosis, intracellular activity, capuramycin, Intracellular Drug Activity, CM Analogues, emulsifiers
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