The human milk protein-lipid complex HAMLET sensitizes bacterial pathogens to traditional antimicrobial agents
Marks, Laura R ; Clementi, Emily A and Hakansson, Anders P LU
(2012)
In PLoS ONE
7(8).
p.43514-43514
- Abstract
The fight against antibiotic resistance is one of the most significant challenges to public health of our time. The inevitable development of resistance following the introduction of novel antibiotics has led to an urgent need for the development of new antibacterial drugs with new mechanisms of action that are not susceptible to existing resistance mechanisms. One such compound is HAMLET, a natural complex from human milk that kills Streptococcus pneumoniae (the pneumococcus) using a mechanism different from common antibiotics and is immune to resistance-development. In this study we show that sublethal concentrations of HAMLET potentiate the effect of common antibiotics (penicillins, macrolides, and aminoglycosides) against... (More)
The fight against antibiotic resistance is one of the most significant challenges to public health of our time. The inevitable development of resistance following the introduction of novel antibiotics has led to an urgent need for the development of new antibacterial drugs with new mechanisms of action that are not susceptible to existing resistance mechanisms. One such compound is HAMLET, a natural complex from human milk that kills Streptococcus pneumoniae (the pneumococcus) using a mechanism different from common antibiotics and is immune to resistance-development. In this study we show that sublethal concentrations of HAMLET potentiate the effect of common antibiotics (penicillins, macrolides, and aminoglycosides) against pneumococci. Using MIC assays and short-time killing assays we dramatically reduced the concentrations of antibiotics needed to kill pneumococci, especially for antibiotic-resistant strains that in the presence of HAMLET fell into the clinically sensitive range. Using a biofilm model in vitro and nasopharyngeal colonization in vivo, a combination of HAMLET and antibiotics completely eradicated both biofilms and colonization in mice of both antibiotic-sensitive and resistant strains, something each agent alone was unable to do. HAMLET-potentiation of antibiotics was partially due to increased accessibility of antibiotics to the bacteria, but relied more on calcium import and kinase activation, the same activation pathway HAMLET uses when killing pneumococci by itself. Finally, the sensitizing effect was not confined to species sensitive to HAMLET. The HAMLET-resistant respiratory species Acinetobacter baumanii and Moraxella catarrhalis were all sensitized to various classes of antibiotics in the presence of HAMLET, activating the same mechanism as in pneumococci. Combined these results suggest the presence of a conserved HAMLET-activated pathway that circumvents antibiotic resistance in bacteria. The ability to activate this pathway may extend the lifetime of the current treatment arsenal.
(Less)
- author
- Marks, Laura R
; Clementi, Emily A
and Hakansson, Anders P
LU
- organization
- publishing date
- 2012
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Animals, Anti-Bacterial Agents, Anti-Infective Agents, Autolysis, Bacteria, Biofilms, Calcium, Coloring Agents, Drug Resistance, Microbial, Erythromycin, Gentamicins, Humans, Lactalbumin, Lipids, Mice, Microscopy, Electron, Scanning, Milk Proteins, Milk, Human, Oleic Acids, Penicillins, Streptococcus pneumoniae
- in
- PLoS ONE
- volume
- 7
- issue
- 8
- pages
- 43514 - 43514
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- pmid:22905269
- scopus:84865056525
- ISSN
- 1932-6203
- DOI
- 10.1371/journal.pone.0043514
- language
- English
- LU publication?
- yes
- id
- e17d53ac-f0ab-4d56-b7fd-35e5043a3393
- date added to LUP
- 2016-05-21 10:49:42
- date last changed
- 2024-03-21 23:46:04
@article{e17d53ac-f0ab-4d56-b7fd-35e5043a3393,
abstract = {{<p>The fight against antibiotic resistance is one of the most significant challenges to public health of our time. The inevitable development of resistance following the introduction of novel antibiotics has led to an urgent need for the development of new antibacterial drugs with new mechanisms of action that are not susceptible to existing resistance mechanisms. One such compound is HAMLET, a natural complex from human milk that kills Streptococcus pneumoniae (the pneumococcus) using a mechanism different from common antibiotics and is immune to resistance-development. In this study we show that sublethal concentrations of HAMLET potentiate the effect of common antibiotics (penicillins, macrolides, and aminoglycosides) against pneumococci. Using MIC assays and short-time killing assays we dramatically reduced the concentrations of antibiotics needed to kill pneumococci, especially for antibiotic-resistant strains that in the presence of HAMLET fell into the clinically sensitive range. Using a biofilm model in vitro and nasopharyngeal colonization in vivo, a combination of HAMLET and antibiotics completely eradicated both biofilms and colonization in mice of both antibiotic-sensitive and resistant strains, something each agent alone was unable to do. HAMLET-potentiation of antibiotics was partially due to increased accessibility of antibiotics to the bacteria, but relied more on calcium import and kinase activation, the same activation pathway HAMLET uses when killing pneumococci by itself. Finally, the sensitizing effect was not confined to species sensitive to HAMLET. The HAMLET-resistant respiratory species Acinetobacter baumanii and Moraxella catarrhalis were all sensitized to various classes of antibiotics in the presence of HAMLET, activating the same mechanism as in pneumococci. Combined these results suggest the presence of a conserved HAMLET-activated pathway that circumvents antibiotic resistance in bacteria. The ability to activate this pathway may extend the lifetime of the current treatment arsenal.</p>}},
author = {{Marks, Laura R and Clementi, Emily A and Hakansson, Anders P}},
issn = {{1932-6203}},
keywords = {{Animals; Anti-Bacterial Agents; Anti-Infective Agents; Autolysis; Bacteria; Biofilms; Calcium; Coloring Agents; Drug Resistance, Microbial; Erythromycin; Gentamicins; Humans; Lactalbumin; Lipids; Mice; Microscopy, Electron, Scanning; Milk Proteins; Milk, Human; Oleic Acids; Penicillins; Streptococcus pneumoniae}},
language = {{eng}},
number = {{8}},
pages = {{43514--43514}},
publisher = {{Public Library of Science (PLoS)}},
series = {{PLoS ONE}},
title = {{The human milk protein-lipid complex HAMLET sensitizes bacterial pathogens to traditional antimicrobial agents}},
url = {{http://dx.doi.org/10.1371/journal.pone.0043514}},
doi = {{10.1371/journal.pone.0043514}},
volume = {{7}},
year = {{2012}},
}