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.
(Less)
- author
- Meikle, Virginia
; Mossberg, Ann-Kristin
LU
; Mitra, Avishek
; Hakansson, Anders P
LU
and Niederweis, Michael
- organization
- publishing date
- 2019-02-01
- 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
- article number
- e01846-18
- publisher
- American Society for Microbiology
- external identifiers
-
- scopus:85060810306
- pmid:30420480
- pmid:30420480
- 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
- 2024-09-17 07:45:29
@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>}},
author = {{Meikle, Virginia and Mossberg, Ann-Kristin and Mitra, Avishek and Hakansson, Anders P and Niederweis, Michael}},
issn = {{1098-6596}},
keywords = {{-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}},
doi = {{10.1128/AAC.01846-18}},
volume = {{63}},
year = {{2019}},
}