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Experimental Therapeutics

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

Virginia Meikle, Ann-Kristin Mossberg, Avishek Mitra, Anders P. Hakansson, Michael Niederweis
Virginia Meikle
Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
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Ann-Kristin Mossberg
Department of Translational Medicine, Division of Experimental Infection Medicine, Lund University, Malmö, Sweden
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Avishek Mitra
Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
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Anders P. Hakansson
Department of Translational Medicine, Division of Experimental Infection Medicine, Lund University, Malmö, Sweden
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Michael Niederweis
Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
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DOI: 10.1128/AAC.01846-18
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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 make M. tuberculosis more 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 against M. 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 against M. tuberculosis. For example, the minimal inhibitory concentrations of rifampin, bedaquiline, delamanid, and clarithromycin were decreased by 8- to 16-fold. HAMLET also killed M. tuberculosis and enhanced the efficacy of TB drugs inside macrophages, a natural habitat of M. 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.

FOOTNOTES

    • Received 28 August 2018.
    • Returned for modification 24 September 2018.
    • Accepted 31 October 2018.
    • Accepted manuscript posted online 12 November 2018.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.01846-18.

  • Copyright © 2019 American Society for Microbiology.

All Rights Reserved.

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A Protein Complex from Human Milk Enhances the Activity of Antibiotics and Drugs against Mycobacterium tuberculosis
Virginia Meikle, Ann-Kristin Mossberg, Avishek Mitra, Anders P. Hakansson, Michael Niederweis
Antimicrobial Agents and Chemotherapy Jan 2019, 63 (2) e01846-18; DOI: 10.1128/AAC.01846-18

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A Protein Complex from Human Milk Enhances the Activity of Antibiotics and Drugs against Mycobacterium tuberculosis
Virginia Meikle, Ann-Kristin Mossberg, Avishek Mitra, Anders P. Hakansson, Michael Niederweis
Antimicrobial Agents and Chemotherapy Jan 2019, 63 (2) e01846-18; DOI: 10.1128/AAC.01846-18
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KEYWORDS

HAMLET
α-lactalbumin
liprotides
macrophages
multidrug resistance
oleic acid
potentiation
sensitization

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