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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.

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author
organization
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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
external identifiers
  • 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
2017-01-01 08:26:44
@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},
  keyword      = {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},
  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},
  volume       = {7},
  year         = {2012},
}