Human organoid biofilm model for assessing antibiofilm activity of novel agents

Bing Catherine Wu,Peter H Nibbering,Alwin E Adriaans,Robert E W Hancock,Evan F Haney,Noushin Akhoundsadegh,Daniel Pletzer,Michael J Trimble

doi:10.1038/s41522-020-00182-4

Abstract

Bacterial biofilms cause 65% of all human infections and are highly resistant to antibiotic therapy but lack specific treatments. To provide a human organoid model for studying host-microbe interplay and enabling screening for novel antibiofilm agents, a human epidermis organoid model with robust methicillin-resistant Staphylococcus aureus (MRSA) USA300 and Pseudomonas aeruginosa PAO1 biofilm was developed. Treatment of 1-day and 3-day MRSA and PAO1 biofilms with antibiofilm peptide DJK-5 significantly and substantially reduced the bacterial burden. This model enabled the screening of synthetic host defense peptides, revealing their superior antibiofilm activity against MRSA compared to the antibiotic mupirocin. The model was extended to evaluate thermally wounded skin infected with MRSA biofilms resulting in increased bacterial load, cytotoxicity, and pro-inflammatory cytokine levels that were all reduced upon treatment with DJK-5. Combination treatment of DJK-5 with an anti-inflammatory peptide, 1002, further reduced cytotoxicity and skin inflammation.

Highlights

There has been considerable discussion concerning the antibiotic resistance threat as resistance and multi-drug resistance rises and insufficient new antibiotics are being discovered[1]
The morphology and architecture of 24 h bacterial skin biofilms were assessed by histological hematoxylin and eosin (H&E) staining, scanning electron microscopy, and confocal laser scanning microscopy
We described the adaptation of an air–liquid interface human skin model as an in vivo-like screening tool for novel agents against biofilm infections such as methicillin-resistant Staphylococcus aureus (MRSA) and P. aeruginosa

Summary

Introduction

There has been considerable discussion concerning the antibiotic resistance threat as resistance and multi-drug resistance rises and insufficient new antibiotics are being discovered[1]. The treatment of biofilm infections often involves surgical debridement and the use of a combination of antibiotics developed for free-swimming (planktonic) bacteria[4,5]. This is problematic because biofilms are adaptively multi-drug resistant, exhibiting inhibitory concentrations that are 10–1000 fold more resistant to virtually all conventional antibiotics[6], and can rapidly recover from surgical debridement[4]. There are no standardized in vitro biofilm tests like the minimal inhibitory concentration assays implemented by the Clinical and Laboratory Standards Institute and animal models of biofilm infections are often complex, of uncertain relevance, and often do not reflect human conditions[8]

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Results

Conclusion