A Protein Complex from Human Milk Enhances the Activity of Antibiotics and Drugs against Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis, 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, has rendered TB untreatable. However, the development of 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 makeM. tuberculosismore susceptible to existing TB drugs. In this study, we show that HAMLET, an α-lactalbumin–oleic acid complex derived from human milk, has bactericidal activity againstM. tuberculosis. HAMLET consists of a micellar oleic acid core surrounded by a shell of partially denatured α-lactalbumin molecules and unloads oleic acid into cells upon contact with lipid membranes. At sublethal concentrations, HAMLET potentiated a remarkably broad array of TB drugs and antibiotics againstM. tuberculosis. For example, the minimal inhibitory concentrations of rifampin, bedaquiline, delamanid, and clarithromycin were decreased by 8- to 16-fold. HAMLET also killedM. tuberculosisand enhanced the efficacy of TB drugs inside macrophages, a natural habitat ofM. tuberculosis. Previous studies showed that HAMLET is stable after oral delivery in mice and nontoxic 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 here.

α-Lactalbumin, Amazing Calcium-Binding Protein

“…Treatment of pneumococci with HAMLET immediately inhibited their ATP and lactate production, suggesting that HAMLET inhibits glycolysis. HAMLET has bactericidal activity against M. tuberculosis [ 295 ]. At sub-lethal concentrations, HAMLET potentiates a remarkably broad array of drugs and antibiotics against M. tuberculosis .…”

Cuando la leche materna puede ser el vehículo de un patógeno

“…Algunas espiroquetas y parásitos sólo pueden ser transmitidos si hay sangramiento mamario al amamantar como es el caso de Chagas 36 .…”

Protein–lipid complexes: molecular structure, current scenarios and mechanisms of cytotoxicity

“…5). 63,[129][130][131][132][133] HAMLET was found to kill certain bacterial strains, such as S. pneumonia, Haemophilus inuenzae, antibiotic-susceptible and -resistant Streptococcus pyogenes (GAS) and Streptococcus agalactiae (GBS), and multidrugresistant Mycobacterium tuberculosis (MD-TB), 128,133,134 and subtoxic doses of HAMLET not only stimulate the bactericidal effect for treatment of pneumococci, 135 but potentiate a remarkably broad array of TB drugs and antibiotics against M. tuberculosis as well as S. pneumoniae, GAS and GBS. The synergistic action of HAMLET on the viability of TB decreased the minimal inhibitory concentrations of rifampin, bedaquiline, delamanid, and clarithromycin by 8-to 16-fold.…”

“…5). 29,133,134,140 Mycobacteria have the lowest known cell permeability among bacteria, 141 while Gram-positive bacteria such as S. pneumoniae have a rather high cell permeability. 142 By a similar mechanism, HAMLET effectively killed many bacterial pathogens, possibly by calcium and/or sodium transport inhibition.…”