Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis (TB), has surpassed HIV/AIDS as the leading cause of death from a single infectious agent. The increasing occurrence of drug resistant strains has become a major challenge for health care systems and, in some cases, rendered TB untreatable. However, developing new TB drugs has been plagued with high failure rates and costs. Alternative strategies to increase the efficacy of current TB treatment regimens include host-directed therapies or agents that make Mtb more susceptible to existing TB drugs. In this study, we show that HAMLET, an alpha-lactalbumin - oleic acid complex derived from human milk, has bactericidal activity against Mtb. HAMLET consists of a micellar oleic acid core surrounded by a shell of partially denatured alpha-lactalbumin molecules and unloads oleic acid into cells upon contact with lipid membranes. At sub-lethal concentrations, HAMLET potentiated a remarkably broad array of TB drugs and antibiotics against Mtb. For example, the minimal inhibitory concentrations of rifampicin, bedaquiline, delamanid and clarithromycin were decreased by 8- to 16-fold. HAMLET also killed Mtb and enhanced the efficacy of TB drugs inside macrophages, a natural habitat of Mtb. Previous studies showed that HAMLET is stable after oral delivery in mice and non-toxic in humans and that it is possible to package hydrophobic compounds in the oleic acid core of HAMLET to increase their solubility and metabolic stability. The potential of HAMLET and other liprotides as drug delivery and sensitization agents in TB chemotherapy is discussed.
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