The Human Milk Protein-Lipid Complex HAMLET Sensitizes Bacterial Pathogens to Traditional Antimicrobial Agents
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{"title"=>"The human milk protein-lipid complex HAMLET sensitizes bacterial pathogens to traditional antimicrobial agents", "type"=>"journal", "authors"=>[{"first_name"=>"Laura R.", "last_name"=>"Marks", "scopus_author_id"=>"55326767300"}, {"first_name"=>"Emily A.", "last_name"=>"Clementi", "scopus_author_id"=>"57190085163"}, {"first_name"=>"Anders P.", "last_name"=>"Hakansson", "scopus_author_id"=>"56404191100"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-84865056525", "pui"=>"365445621", "doi"=>"10.1371/journal.pone.0043514", "isbn"=>"1932-6203", "sgr"=>"84865056525", "pmid"=>"22905269"}, "id"=>"8923473f-0050-39a6-b6d5-5fdd664f546d", "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 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.", "link"=>"http://www.mendeley.com/research/human-milk-proteinlipid-complex-hamlet-sensitizes-bacterial-pathogens-traditional-antimicrobial-agen", "reader_count"=>35, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Researcher"=>3, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>1, "Other"=>2, "Student > Master"=>3, "Student > Bachelor"=>8, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Researcher"=>3, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>1, "Other"=>2, "Student > Master"=>3, "Student > Bachelor"=>8, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Nursing and Health Professions"=>1, "Biochemistry, Genetics and Molecular Biology"=>3, "Agricultural and Biological Sciences"=>21, "Medicine and Dentistry"=>4, "Veterinary Science and Veterinary Medicine"=>1, "Chemistry"=>1, "Immunology and Microbiology"=>2, "Energy"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Chemistry"=>{"Chemistry"=>1}, "Energy"=>{"Energy"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>21}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>1}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>1}}, "reader_count_by_country"=>{"Netherlands"=>1, "United States"=>1, "Chile"=>1, "Germany"=>1}, "group_count"=>3}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/591829"], "description"=>"<p>(A) <i>S. pneumoniae</i> D39 were incubated with Alexa Fluor 488-gentamicin in the presence or absence of HAMLET. HAMLET significantly increased the cell-associated level of gentamicin. (B) The penicillin-resistant strain SP670 and the penicillin-sensitive strain D39 were incubated with the fluorescent beta-lactam Bocillin FL in the presence or absence of HAMLET. HAMLET did not increase the cell-associated level of Bocillin FL in either strain. The results are based on three individual experiments with duplicate samples. Statistics was performed using the unpaired Student t-test. Significance was indicated as follows: ** = P<0.01, *** = P<0.001, ns  =  not significant.</p>", "links"=>[], "tags"=>["hamlet", "uptake", "binding", "gentamicin", "bocillin"], "article_id"=>262316, "categories"=>["Cell Biology", "Microbiology", "Biochemistry", "Infectious Diseases", "Pharmacology", "Biotechnology"], "users"=>["Laura R. Marks", "Emily A. Clementi", "Anders P. Hakansson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0043514.g005", "stats"=>{"downloads"=>2, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Impact_of_HAMLET_on_uptake_and_binding_of_gentamicin_and_Bocillin_FL_/262316", "title"=>"Impact of HAMLET on uptake and binding of gentamicin and Bocillin FL.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 00:50:50"}
  • {"files"=>["https://ndownloader.figshare.com/files/591717"], "description"=>"<p>(A and B) Mice were colonized with <i>S. pneumoniae</i> EF3030 for 48 hours, treated intranasally with various doses of gentamicin in the presence (red circles) or absence (black squares) of HAMLET (50 µg) for 6 hours, and the bacterial burden associated with the nasal lavage (A) and the nasopharyngeal tissue (B) was determined. Bacteria in nasal lavage and associated with the nasopharyngeal tissue were significantly more sensitive to gentamicin/HAMLET combination therapy than gentamicin alone. (C and D) Mice were colonized with the penicillin-resistant strain <i>S. pneumoniae</i> SP670 (MIC  = 4 µg/mL) for 48 hours, treated intranasally with various doses of penicillin G in the presence (red circles) or absence (black squares) of HAMLET (50 µg) for 12 hours and the bacterial burden associated with the nasal lavage (C) and the nasopharyngeal tissue (D) was determined. Penicillin G alone had no effect on the bacterial burden in either the nasal lavage or in the tissue. However, combination therapy with HAMLET and penicillin caused a dose-dependent decrease in bacterial burden leading to eradication of colonization. The graph shows colonization data for individual mice, with the mean recovered bacteria and the standard deviation depicted. The results are based on experiments using groups of 6–10 mice. Statistics was performed using the unpaired Student t-test. Significance was indicated as follows: * = <i>P</i><0.05, ** = <i>P</i><0.01, ns  =  non-significant.</p>", "links"=>[], "tags"=>["eradicates", "pneumococci", "nasopharyngeal"], "article_id"=>262216, "categories"=>["Cell Biology", "Microbiology", "Biochemistry", "Infectious Diseases", "Pharmacology", "Biotechnology"], "users"=>["Laura R. Marks", "Emily A. Clementi", "Anders P. Hakansson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0043514.g004", "stats"=>{"downloads"=>5, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HAMLET_antibiotic_combination_treatment_eradicates_pneumococci_during_nasopharyngeal_colonization_/262216", "title"=>"HAMLET-antibiotic combination treatment eradicates pneumococci during nasopharyngeal colonization.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 00:50:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/591987"], "description"=>"<p>(A) Optical density at 600 nm of <i>S. pneumoniae</i> D39 (black line) after exposure to a lethal concentration of HAMLET (250 µg/ml; red line), a sublethal concentration of HAMLET (50 µg/ml; blue line), a sublethal concentration of gentamicin (50 µg/mL; green line) or the combination of sublethal concentrations of HAMLET and gentamicin (purple line) that resulted in complete death of the inoculum. The data shows a representative experiment. (B) Representative scanning electron micrographs of untreated <i>S. pneumoniae</i> D39, as well as bacteria treated 4 minutes with a lethal concentration of HAMLET (250 µg/mL), one hour with a similarly lethal concentration of gentamicin (500 µg/mL) or one hour with a sublethal concentration of HAMLET (50 µg/mL) or a sublethal concentration of gentamicin (50 µg/mL) in combination (HL + Gent). Note the numerous defects of the pneumococcal cell wall after exposure to HAMLET or gentamicin alone compared with the structurally intact cells after exposure to the combination of the two agents.</p>", "links"=>[], "tags"=>["hamlet-gentamicin"], "article_id"=>262484, "categories"=>["Cell Biology", "Microbiology", "Biochemistry", "Infectious Diseases", "Pharmacology", "Biotechnology"], "users"=>["Laura R. Marks", "Emily A. Clementi", "Anders P. Hakansson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0043514.g007", "stats"=>{"downloads"=>3, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Autolysis_during_HAMLET_gentamicin_combination_therapy_/262484", "title"=>"Autolysis during HAMLET-gentamicin combination therapy.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 00:51:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/591449"], "description"=>"<p><i>S. pneumoniae</i> D39 were grown in broth for 16 hours in the presence of penicillin G (A) or gentamicin (B) with and without the addition of HAMLET. The figure shows representative growth curves for the lowest concentration of antibiotic and HAMLET that inhibited bacterial growth by combination treatment without either agent alone affecting growth.</p>", "links"=>[], "tags"=>["lowers", "mics", "erythromycin"], "article_id"=>261937, "categories"=>["Cell Biology", "Microbiology", "Biochemistry", "Infectious Diseases", "Pharmacology", "Biotechnology"], "users"=>["Laura R. Marks", "Emily A. Clementi", "Anders P. Hakansson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0043514.g001", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HAMLET_lowers_the_MICs_of_gentamicin_erythromycin_and_penicillin_/261937", "title"=>"HAMLET lowers the MICs of gentamicin, erythromycin and penicillin.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 00:48:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/592060"], "description"=>"*<p>HL (HAMLET) used at a concentration of 0.75X MIC (15 µg/mL).</p>**<p>HL (HAMLET) used at a concentration of 0.85X MIC (17 µg/mL).</p>***<p>HAMLET used at a concentration of 50 µg/mL.</p>", "links"=>[], "tags"=>["Infectious diseases", "microbiology", "biotechnology", "pharmacology", "obstetrics", "Biochemistry"], "article_id"=>262553, "categories"=>["Cell Biology", "Microbiology", "Biochemistry", "Infectious Diseases", "Pharmacology", "Biotechnology"], "users"=>["Laura R. Marks", "Emily A. Clementi", "Anders P. Hakansson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0043514.t001", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MIC_determination_of_HAMLET_antibiotic_combination_therapy_/262553", "title"=>"MIC determination of HAMLET/antibiotic combination therapy.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-20 00:52:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/591898"], "description"=>"<p>(A) <i>S. pneumoniae</i> D39 were treated with a lethal concentration of HAMLET (12X MIC) in the absence of inhibitor (HL) or presence of 20 μM staurosporine (HL + Sts), or 30 µM ruthenium red (HL + RuR) for 1 hour at 37°C. The treated bacteria were diluted and plated on blood agar plates and viable CFU/ml were determined after overnight growth. (B and C) <i>S. pneumoniae</i> D39 were treated with 50 µg/mL HAMLET (HL), 50 µg/mL gentamicin (Gent), 20 µg/mL penicillin G (PcG), or a combination of gentamicin and HAMLET or penicillin G and HAMLET in the absence (HL + Gent, HL + PcG) or presence of 20 μM staurosporine (Sts), or 30 µM ruthenium red (RuR) for 1 hour at 37°C. The treated bacteria were diluted and plated on blood agar plates and viable CFU/ml were determined after overnight growth. The graph depicts the log<sub>10</sub> death induced by each treatment and showed that staurosporine and ruthenium red significantly reduced HAMLET-induced death (A) and also significantly blocked HAMLET's ability to sensitize pneumococci to gentamicin (B) and penicillin G (C). The results are based on three individual experiments with duplicate samples. Statistics was performed using the unpaired Student t-test. Significance was indicated as follows: *** = <i>P</i><0.001.</p>", "links"=>[], "tags"=>["calcium", "kinase", "inhibitors", "hamlet-induced", "sensitization", "pneumococci"], "article_id"=>262392, "categories"=>["Cell Biology", "Microbiology", "Biochemistry", "Infectious Diseases", "Pharmacology", "Biotechnology"], "users"=>["Laura R. Marks", "Emily A. Clementi", "Anders P. Hakansson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0043514.g006", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_calcium_and_kinase_inhibitors_on_HAMLET_induced_sensitization_of_pneumococci_to_gentamicin_/262392", "title"=>"Effect of calcium and kinase inhibitors on HAMLET-induced sensitization of pneumococci to gentamicin.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 00:51:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/591590"], "description"=>"<p>The activity of penicillin G (100 µg/mL), HAMLET (250 µg/mL), or the combination of both agents were tested on <i>in vitro</i> biofilms of the penicillin-sensitive strain D39 (A) or the penicillin-resistant strain SP670 (B) formed over a prefixed epithelium of NCI-H292 cells and were tested by determining the bacterial death (in log<sub>10</sub>) after culturing bacterial dilutions overnight on blood agar. Similarly, the activity of erythromycin (250 µg/mL), HAMLET (250 µg/mL), or the combination of both agents on <i>in vitro</i> biofilms of the erythromycin-sensitive strain D39 (C) or the erythromycin-resistant strain D39-P2A1 (D) were tested in a similar fashion as was the activity of 200 µg/ml gentamicin (E) or 500 µg/ml gentamicin (F) alone or in combination with 100 µg/ml HAMLET (100 µg/mL) over 3 hours on pre-established biofilms formed by the strain EF3030. The results are based on three individual experiments with duplicate samples. Statistics was performed using the paired Student t-test. Significance was indicated as follows: * = <i>P</i><0.05, ** = <i>P</i><0.01. To visualize the morphology of the treated biofilms, SEM studies were performed. Images show (G) the structure of an untreated 48 hour EF3030 biofilm, (H) an EF3030 biofilm after 3 hour treatment with 500 µg/mL gentamicin alone, (I) an EF3030 biofilm after 3 hour treatment with HAMLET (100 µg/mL) alone and (J) an EF3030 biofilm after 3 hour treatment with the combination of 100 µg/mL HAMLET and 500 µg/mL Gentamicin. An epithelial substratum prior to biofilm formation has been included as a control (insert in panel J). The increased bactericidal activity of the combination treatment was associated with a reduction in the density of adherent bacteria and biofilm matrix.</p>", "links"=>[], "tags"=>["vitro", "biofilm"], "article_id"=>262092, "categories"=>["Cell Biology", "Microbiology", "Biochemistry", "Infectious Diseases", "Pharmacology", "Biotechnology"], "users"=>["Laura R. Marks", "Emily A. Clementi", "Anders P. Hakansson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0043514.g003", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_effect_of_HAMLET_antibiotic_combination_treatment_on_in_vitro_biofilm_viability_/262092", "title"=>"The effect of HAMLET/antibiotic combination treatment on in vitro biofilm viability.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 00:49:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/591512"], "description"=>"<p>Short-time killing of the penicillin-sensitive strain D39 (A) by penicillin G (20 µg/mL), HAMLET (50 µg/mL) and penicillin combined with HAMLET over 4 hours. (B) Killing of the penicillin-resistant strain SP670 by penicillin G (20 or 30 µg/mL), HAMLET (50 µg/mL), or penicillin G combined with HAMLET over 4 hours. (C) Killing of the erythromycin-sensitive strain D39 by erythromycin (200 µg/mL), HAMLET (50 µg/mL), or erythromycin combined with HAMLET over 4 hours. (D) Killing of the erythromycin-resistant D39-derivative JY53 by erythromycin (200 µg/mL), HAMLET (50 µg/mL), or erythromycin combined with HAMLET over 4 hours. (E) Killing of D39 by gentamicin (50 µg/mL), HAMLET (50 µg/mL), or gentamicin combined with HAMLET over 1 hour. The results are based on three individual experiments with duplicate samples and are expressed as means ± S.D. Statistics was performed using the unpaired Student t-test. Significance was indicated as follows: * = <i>P</i><0.05, ** = <i>P</i><0.01, *** =  <i>P</i><0.001, ns  =  not significant.</p>", "links"=>[], "tags"=>["short-time", "pneumococcal", "penicillin", "erythromycin"], "article_id"=>262003, "categories"=>["Cell Biology", "Microbiology", "Biochemistry", "Infectious Diseases", "Pharmacology", "Biotechnology"], "users"=>["Laura R. Marks", "Emily A. Clementi", "Anders P. Hakansson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0043514.g002", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Potentiation_of_short_time_pneumococcal_killing_by_gentamicin_penicillin_and_erythromycin_in_the_presence_of_HAMLET_/262003", "title"=>"Potentiation of short-time pneumococcal killing by gentamicin, penicillin and erythromycin in the presence of HAMLET.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 00:49:11"}

PMC Usage Stats | Further Information

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Relative Metric

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