title: Synergistic Photothermal and Antibiotic Killing of Biofilm-AssociatedStaphylococcus aureusUsing Targeted Antibiotic-Loaded Gold Nanoconstructs.
abstract: Resistance to conventional antibiotics is a growing public health concern that is quickly outpacing the development of new antibiotics. This has led the Infectious Diseases Society of America (IDSA) to designateEnterococcus faecium,Staphylococcus aureus,Klebsiella pneumoniae,Acinetobacter baumannii,Pseudomonas aeruginosa, andEnterobacterspecies as "ESKAPE pathogens" on the basis of the rapidly decreasing availability of useful antibiotics. This emphasizes the urgent need for alternative therapeutic strategies to combat infections caused by these and other bacterial pathogens. In this study, we usedStaphylococcus aureus(S. aureus) as a proof-of-principle ESKAPE pathogen to demonstrate that an appropriate antibiotic (daptomycin) can be incorporated into polydopamine-coated gold nanocages (AuNC@PDA) and that daptomycin-loaded AuNC@PDA can be conjugated to antibodies targeting a species-specific surface protein (staphylococcal protein A; Spa) as a means of achieving selective delivery of the nanoconstructs directly to the bacterial cell surface. Targeting specificity was confirmed by demonstrating a lack of binding to mammalian cells, reduced photothermal and antibiotic killing of the Spa-negative speciesStaphylococcus epidermidis, and reduced killing ofS. aureusin the presence of unconjugated anti-Spa antibodies. We demonstrate that laser irradiation at levels within the current safety standard for use in humans can be used to achieve both a lethal photothermal effect and controlled release of the antibiotic, thus resulting in a degree of therapeutic synergy capable of eradicating viableS. aureuscells. The system was validated using planktonic bacterial cultures of both methicillin-sensitive and methicillin-resistantS. aureusstrains and subsequently shown to be effective in the context of an established biofilm, thus indicating that this approach could be used to facilitate the effective treatment of intrinsically resistant biofilm infections.
authors.affiliation: Department of Microbiology & Immunology, University of Arkansas for Medical Sciences , Little Rock, Arkansas 72205, United States.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Meeker
authors.affiliation: Department of Chemistry and Biochemistry, University of Arkansas , Fayetteville, Arkansas 72701, United States.
authors.forename: Samir V
authors.initials: SV
authors.lastname: Jenkins
authors.affiliation: Department of Chemistry and Biochemistry, University of Arkansas , Fayetteville, Arkansas 72701, United States.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Miller
authors.affiliation: Department of Microbiology & Immunology, University of Arkansas for Medical Sciences , Little Rock, Arkansas 72205, United States.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Beenken
authors.affiliation: Department of Microbiology & Immunology, University of Arkansas for Medical Sciences , Little Rock, Arkansas 72205, United States.
authors.forename: Allister J
authors.initials: AJ
authors.lastname: Loughran
authors.affiliation: Department of Biomedical Engineering, University of Arkansas , Fayetteville, Arkansas 72701, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Powless
authors.affiliation: Department of Biomedical Engineering, University of Arkansas , Fayetteville, Arkansas 72701, United States.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Muldoon
authors.affiliation: Phillips Classic Laser and Nanomedicine Laboratories, University of Arkansas for Medical Sciences , Little Rock, Arkansas 72205, United States.
authors.forename: Ekaterina I
authors.initials: EI
authors.lastname: Galanzha
authors.affiliation: Phillips Classic Laser and Nanomedicine Laboratories, University of Arkansas for Medical Sciences , Little Rock, Arkansas 72205, United States.
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Zharov
authors.affiliation: Department of Microbiology & Immunology, University of Arkansas for Medical Sciences , Little Rock, Arkansas 72205, United States.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Smeltzer
authors.affiliation: Department of Chemistry and Biochemistry, University of Arkansas , Fayetteville, Arkansas 72701, United States.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Chen
keywords: antimicrobial; biofilm; daptomycin; gold nanocages; methicillin-resistant Staphylococcus aureus; polydopamine