Synergistic antibacterial effect of co-administering adipose-derived mesenchymal stromal cells and Ophiophagus hannah l-amino acid oxidase in a mouse model of methicillin-resistant Staphylococcus aureus-infected wounds

Abstract

BackgroundMesenchymal stromal cells (MSCs) and Ophiophagus hannah l-amino acid oxidase (Oh-LAAO) have been reported to exhibit antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA). Published data have indicated that synergistic antibacterial effects could be achieved by co-administration of two or more antimicrobial agents. However, this hypothesis has not been proven in a cell- and protein-based combination. In this study, we investigate if co-administration of adipose-derived MSCs and Oh-LAAO into a mouse model of MRSA-infected wounds would be able to result in a synergistic antibacterial effect.MethodsMSCs and Oh-LAAO were isolated and characterized by standard methodologies. The effects of the experimental therapies were evaluated in C57/BL6 mice. The animal study groups consisted of full-thickness uninfected and MRSA-infected wound models which received Oh-LAAO, MSCs, or both. Oh-LAAO was administered directly on the wound while MSCs were delivered via intradermal injections. The animals were housed individually with wound measurements taken on days 0, 3, and 7. Histological analyses and bacterial enumeration were performed on wound biopsies to determine the efficacy of each treatment.ResultsImmunophenotyping and differentiation assays conducted on isolated MSCs indicated expression of standard cell surface markers and plasticity which corresponds to published data. Characterization of Oh-LAAO by proteomics, enzymatic, and antibacterial assays confirmed the identity, purity, and functionality of the enzyme prior to use in our subsequent studies. Individual treatments with MSCs and Oh-LAAO in the infected model resulted in reduction of MRSA load by one order of magnitude to the approximate range of 6 log10 colony-forming units (CFU) compared to untreated controls (7.3 log10 CFU). Similar wound healing and improvements in histological parameters were observed between the two groups. Co-administration of MSCs and Oh-LAAO reduced bacterial burden by approximately two orders of magnitude to 5.1 log10 CFU. Wound closure measurements and histology analysis of biopsies obtained from the combinational therapy group indicated significant enhancement in the wound healing process compared to all other groups.ConclusionsWe demonstrated that co-administration of MSCs and Oh-LAAO into a mouse model of MRSA-infected wounds exhibited a synergistic antibacterial effect which significantly reduced the bacterial count and accelerated the wound healing process.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0457-2) contains supplementary material, which is available to authorized users.

Broad-Spectrum Antibacterial Effects of Human Adipose-Derived Stromal Cells

“…Although surprising, the hyperpolarization observed for Ec is also a marker of the loss of bacterial viability as previously reported, for example, during alkaline stress, proton capture, and ATP hyperconsumption [18]. Increasing bacterial permeability may be a strategy to promote antibiotic action on resistant strains [19, 20]. Indeed, we demonstrated that ASCs enhanced the action of ampicillin and metronidazole on Fn .…”

Antimicrobial activity and synergism of ursolic acid 3-O-α-L-arabinopyranoside with oxacillin against methicillin-resistant Staphylococcus aureus

“…This also indicated that URS restored the susceptibility of MRSA to OXA (11). Combination therapy is an urgently recommended empirical treatment for bacterial infections and for preventing the emergence of resistant mutant strains of bacteria (37,38). The time-kill growth curves further confirmed the synergism between URS and OXA at sub-inhibitory concentrations (Fig.…”

Combined therapy of photobiomodulation and adipose-derived stem cells synergistically improve healing in an ischemic, infected and delayed healing wound model in rats with type 1 diabetes mellitus

“…Therefore, the observed occurrence and adaptation of MRSA in DFUs9 has stemmed from a growing range of non-curable staphylococcal contaminations 46. Novel approaches to treat MRSA contamination and counter the growing complication of MRSA are mandatory 34. Specifically, our experiment aimed to focus on the bactericidal effects of PBM47 and ADS34 because both have been individually reported to have bactericidal effects in animal models.…”

“…Novel approaches to treat MRSA contamination and counter the growing complication of MRSA are mandatory 34. Specifically, our experiment aimed to focus on the bactericidal effects of PBM47 and ADS34 because both have been individually reported to have bactericidal effects in animal models. To date, there is no probe that has examined the effects of PBM on immunomodulation of ADS.…”

“…At 24 hours after surgery, we mixed 1×10 6 passage-4 ADS cells34 in 300 µL PBS 31. The mixture was immediately injected intradermally by an insulin syringe into eight sites around each wound at a 4–5 mm distance from the wound’s margin (figure 1).…”