title: Sensitization of Staphylococcus aureus to methicillin and other antibiotics in vitro and in vivo in the presence of HAMLET.
abstract: HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a protein-lipid complex from human milk with both tumoricidal and bactericidal activities. HAMLET exerts a rather specific bactericidal activity against some respiratory pathogens, with highest activity against Streptococcus pneumoniae, but lacks activity against most other bacterial pathogens, including Staphylococci. Still, ion transport associated with death in S. pneumoniae is also detected to a lower degree in insensitive organisms. In this study we demonstrate that HAMLET acts as an antimicrobial adjuvant that can increase the activity of a broad spectrum of antibiotics (methicillin, vancomycin, gentamicin and erythromycin) against multi-drug resistant Staphylococcus aureus, to a degree where they become sensitive to those same antibiotics, both in antimicrobial assays against planktonic and biofilm bacteria and in an in vivo model of nasopharyngeal colonization. We show that HAMLET exerts these effects specifically by dissipating the proton gradient and inducing a sodium-dependent calcium influx that partially depolarizes the plasma membrane, the same mechanism induced during pneumococcal death. These effects results in an increased cell associated binding and/or uptake of penicillin, gentamicin and vancomycin, especially in resistant stains. Finally, HAMLET inhibits the increased resistance of methicillin seen under antibiotic pressure and the bacteria do not become resistant to the adjuvant, which is a major advantageous feature of the molecule. These results highlight HAMLET as a novel antimicrobial adjuvant with the potential to increase the clinical usefulness of antibiotics against drug resistant strains of S. aureus.
authors: Department of Microbiology and Immunology, University at Buffalo, State University of New York, Buffalo, New York, United States of America.
authors: Laura R
authors: LR
authors: Marks
authors: Emily A
authors: EA
authors: Clementi
authors: Anders P
authors: AP
authors: Hakansson
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects; D001896:Boron Compounds / Q000378:metabolism / Q000494:pharmacology; D020013:Calcium Signaling; D004357:Drug Synergism; D005839:Gentamicins / Q000494:pharmacology; D007768:Lactalbumin / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008712:Methicillin / Q000494:pharmacology*; D016106:Methicillin Resistance; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D009305:Nasopharynx / Q000382:microbiology; D009829:Oleic Acids / Q000494:pharmacology*; D010406:Penicillins / Q000378:metabolism / Q000494:pharmacology; D012141:Respiratory Tract Infections / Q000517:prevention & control; D013203:Staphylococcal Infections / Q000517:prevention & control; D014475:Uncoupling Agents / Q000494:pharmacology; D014640:Vancomycin / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; C118961:BOCILLIN FL; D001896:Boron Compounds; D005839:Gentamicins; C506422:HAMLET complex, human; D009829:Oleic Acids; D010406:Penicillins; D014475:Uncoupling Agents; D014640:Vancomycin; D007768:Lactalbumin; D008712:Methicillin
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