Recent Developments in Nitric Oxide Donors and Delivery for Antimicrobial and Anti-Biofilm Applications

Abstract

The use of nitric oxide (NO) is emerging as a promising, novel approach for the treatment of antibiotic resistant bacteria and biofilm infections. Depending on the concentration, NO can induce biofilm dispersal, increase bacteria susceptibility to antibiotic treatment, and induce cell damage or cell death via the formation of reactive oxygen or reactive nitrogen species. The use of NO is, however, limited by its reactivity, which can affect NO delivery to its target site and result in off-target effects. To overcome these issues, and enable spatial or temporal control over NO release, various strategies for the design of NO-releasing materials, including the incorporation of photo-activable, charge-switchable, or bacteria-targeting groups, have been developed. Other strategies have focused on increased NO storage and delivery by encapsulation or conjugation of NO donors within a single polymeric framework. This review compiles recent developments in NO drugs and NO-releasing materials designed for applications in antimicrobial or anti-biofilm treatment and discusses limitations and variability in biological responses in response to the use of NO for bacterial eradiation.

Keywords: antibacterial; biofilm; nitric oxide; nitric oxide donors.

Figure 1

Examples of commonly used NO-donors, hybrid and macromolecular NO-releasing designs [21,22,23,24,25,26] NO at various concentrations can exert antimicrobial effects and/or potentiate the activity of antimicrobials.

Figure 2

Synthesis, design, and mechanism of the surface charge switchable α-CD-Ce6-NO-DA, which carried a negative surface charge at pH 7.4, but positive surface charge at pH 5.5, in turn promoting efficient penetration of the supramolecular nanocarrier into biofilm. NO is released from α-CD-Ce6-NO-DA upon reaction with biofilm GSH, which depletes biofilm GSH. ROS is generated upon 660 nm laser irradiation, which could react with NO and further improve PDT efficiency. Reproduced with permission from [134].

Figure 3

Preparation and mechanism of action of Ce6@Arg-ADP. NO release is tunable with NIR irradiation duration. The NO generated can both eradicate wound bacteria and promote wound healing. Reproduced with permission from [137].

Figure 4

Mechanism of action of PDT-, PTT-, and NO-mediated killing of bacteria and eradication of biofilm by AI-MDPA. NIR irradiation generates heat, ROS, and NO that sensitizes bacterial cells to hyperthermia. Reproduced with permission from [135].