Visible-Light-Triggered Self-Reporting Release of Nitric Oxide (NO) for Bacterial Biofilm Dispersal

Abstract

Bacterial infection poses a massive threat to our society, and bacterial biofilm is a major cause of chronic and recurrent infections. The treatment of bacterial biofilms represents a challenging task, and the development of antibacterial materials that can not only disperse bacterial biofilms but also kill bacteria is of increasing interest. Herein, we report the fabrication of well-defined nitric oxide (NO)-releasing amphiphiles, poly­(ethylene oxide)-b-polyCouNO (PEO-b-PCouNO), where CouNO is an N-nitrosoamine-based NO donor containing a coumarin chromophore, exhibiting visible-light-mediated and self-reporting NO-release behavior. Unlike conventional polymeric NO donors derived from N-diazeniumdiolate (NONOates) or N-nitrosothiol (SNOs) that could be only synthesized via the postmodification procedure due to poor stability, the newly developed N-nitrosoamine-based NO donors can be directly polymerized into amphiphiles using reversible addition-fragmentation chain transfer (RAFT) polymerization. The NO-releasing amphiphiles self-assembled into micelles and selective NO release in aqueous medium was achieved by irradiating the micelle solution with visible light, which was characterized by a remarkable fluorescence turn-on (>185-fold), thereby enabling in situ self-reporting NO release. The photoinduced NO release can efficiently disperse bacterial biofilm of Pseudomonas aeruginosa. Moreover, antibiotics (e.g., Ciprofloxacin, Cip) could be loaded into the NO-releasing micelles, and co-delivery of NO and Cip was achieved, allowing for simultaneous biofilm dispersal and bacterial killing. This work provides a new strategy to fabricate macromolecular NO donors, which can efficiently avoid uncontrolled NO leakage and display promising antibacterial applications.

Nitric Oxide-Releasing Polymeric Materials for Antimicrobial Applications: A Review

“…N -nitrosoamine-based NO donors are also photo-triggered NO donors and several small molecular N -nitrosoamine-based NO donors have been explored [141,142,143,144,145]. More recently, Hu et al reported a NO releasing micelle bearing visible light responsive NO donors [146]. Unlike the conventional preparation of NO releasing polymers which usually need postmodification approaches, controlled chain length of N -nitrosoamine-based NO releasing monomers were polymerized by utilizing RAFT polymerization with a polyethylene glycol modified chain transfer agent.…”

“…Fabrication of visible light responsive micelles, and the co-release of NO and Cip under irradiation of 410 nm light to concurrently disperse biofilms and kill bacteria. Reproduced with permission from [146]. Copyright 2019, American Chemical Society.…”

Approaches for the inhibition and elimination of microbial biofilms using macromolecular agents

“…A recent report by Hu and Yu et al described a new, distinct type of NO donor based on a photoresponsive coumarincontaining monomer, whose secondary amine moiety could be loaded with NO upon treatment with the gaseous biocide. 193 The monomer could be directly polymerized in a RAFT chain extension process, starting from a poly(ethylene glycol) macro chain transfer agent, to form amphiphilic block copolymers. These formed selfassembled micelles with NO-loaded hydrophobic cores in aqueous solution.…”

Optimization of nitric oxide donors for investigating biofilm dispersal response in Pseudomonas aeruginosa clinical isolates

“…Along with these, many studies were also carried out to explore novel methods for NO delivery, such as incorporating NO donors into nanoparticles and polymer coating (Sadrearhami et al 2017 ; Duong et al 2014a ; Nablo and Schoenfisch 2003 ; Nablo et al 2005 ). However, more often than not these studies tested different concentrations of NO donors towards early stage biofilms formed by type strains, or did not specify optimal treatment time which is crucial for the interpretation of data from young biofilms to distinguish between prevention and dispersal (Barraud et al 2009a ; Barnes et al 2013 ; Sadrearhami et al 2017 ; Duong et al 2014a ; Shen et al 2019 ; Duong et al 2014b ; Zhu et al 2018 ; Marvasi et al 2014 ). To this end, we systematically compared the optimal concentrations and treatment time of 7 NO donors for triggering biofilm dispersal using P. aeruginosa PAO1, including SNP, S-nitroso-glutathione (GSNO), S-nitroso-N-acetyl-DL-penicillamine (SNAP), 1-(hydroxy-NNO-azoxy)-L-proline (PROLI NONOate), 6-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-hexanamine (MAHMA NONOate), (Z)-1-[N-[3-aminopropyl]-N-[4-(3-aminopropylammonio)butyl]-amino]diazen-1-ium-1,2-diolate (Spermine NONOate) and diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate).…”