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A protein complex from human milk enhances the activity of antibiotics and drugs against Mycobacterium tuberculosis

Meikle, Virginia; Mossberg, Ann-Kristin LU ; Mitra, Avishek; Hakansson, Anders P LU and Niederweis, Michael (2019) In Antimicrobial Agents and Chemotherapy 63(2).
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 -lactalbumin–oleic acid complex derived from human milk, has bactericidal activity against M. tuberculosis.... (More)

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 -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 -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.

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author
organization
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type
Contribution to journal
publication status
published
subject
keywords
-lactalbumin, HAMLET, Liprotides, Macrophages, Multidrug resistance, Oleic acid, Potentiation, Sensitization
in
Antimicrobial Agents and Chemotherapy
volume
63
issue
2
publisher
American Society for Microbiology
external identifiers
  • scopus:85060810306
ISSN
1098-6596
DOI
10.1128/AAC.01846-18
language
English
LU publication?
yes
id
27b849ed-baae-4522-8d2f-87eae71553c1
date added to LUP
2018-11-19 19:16:56
date last changed
2019-03-08 03:05:55
@article{27b849ed-baae-4522-8d2f-87eae71553c1,
  abstract     = {<p>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 -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 -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.</p>},
  articleno    = {e01846-18},
  author       = {Meikle, Virginia and Mossberg, Ann-Kristin and Mitra, Avishek and Hakansson, Anders P and Niederweis, Michael},
  issn         = {1098-6596},
  keyword      = {-lactalbumin,HAMLET,Liprotides,Macrophages,Multidrug resistance,Oleic acid,Potentiation,Sensitization},
  language     = {eng},
  month        = {02},
  number       = {2},
  publisher    = {American Society for Microbiology},
  series       = {Antimicrobial Agents and Chemotherapy},
  title        = {A protein complex from human milk enhances the activity of antibiotics and drugs against Mycobacterium tuberculosis},
  url          = {http://dx.doi.org/10.1128/AAC.01846-18},
  volume       = {63},
  year         = {2019},
}