Ruthenium‐based Photoactive Metalloantibiotics^†

Abstract

Antibiotic resistance is one of the world's most urgent public health problems. Antimicrobial photodynamic therapy (aPDT) is a promising therapy to combat the growing threat of antibiotic resistance. The aPDT combines a photosensitizer and light to generate reactive oxygen species to induce bacterial inactivation. Ruthenium polypyridyl complexes are significant because they possess unique photophysical properties that allow them to produce reactive oxygen species upon photoirradiation, which leads to cytotoxicity. These antimicrobial agents cause bacterial cell death by DNA and cytoplasmic membrane damage. This article presents a comprehensive review of photoactive antimicrobial properties of kinetically inert and labile ruthenium complexes, nanoparticles coupled photoactive ruthenium complexes, and photoactive ruthenium nanoparticles. Additionally, limitations of current ruthenium‐based photoactive antimicrobial agents and future directions for the development of antibiotic‐resistant photoactive antimicrobial agents are discussed. It is important to raise awareness for the ruthenium‐based aPDT agents in order to develop a new class of photoactive metalloantibiotics capable of combating antibiotic resistance.

Antimicrobial Photodynamic Therapy: Latest Developments with a Focus on Combinatory Strategies

“…Quite recently, several metal compounds were characterized for their activity in aPDT. For instance, platinum(II), molybdenum(II), ruthenium(II), cobalt(II), and iridium(III) were proposed as new classes of stable photo-activatable metal complexes capable of combating AMR [11,[103][104][105][106][107][108]. In particular, many mononuclear and polynuclear Ru(II/III) complexes have been considered as potential antibiotics, antifungals, antiparasitics, or antivirals, which have been recently extensively reviewed [107].…”

“…Overall, this multipurpose role of the nanomoiety may include avoiding aggregation (e.g., dimerization, trimerization) and correlated PS quenching, enhancing "solubility" (i.e., dispersibility), stability and bioavailability, allowing "biological stealth", on-demand release and target specificity, and ultimately triggering eventual synergistic aPDT activity with the complementary or ameliorative intrinsic properties of the nanocomponent; although irrevocably confirmed in many nano-PSs, the mechanisms involved in the synergy may differ from one system to another, and often remain partly or integrally unresolved due to the complexity of these tacit multiparameter contextures [113]. It is noteworthy that most systems comprise "classic"/"traditional" organic PSs (natural or synthetic, e.g., curcumin, MB) with fewer examples involving metallated PS molecules such as the recent review from Jain et al dedicated to ruthenium-based photoactive metalloantibiotics [108]. Among aPDT nanomaterials, we can thus identify various families of nanoplatforms based on the nature of the nanocore, starting here with the inorganic vectors followed by the organic templates; as an indication, in the common cases of "multi-component nano-PSs", the classification has been defined hereafter according to the main/prominent nano building block involved in the composition, i.e., metal-based systems, silicon-based systems, carbon-based systems, lipid-based systems, and polymer-based systems.…”

“…Moreover, gold NPs display biocompatibility, low toxicity, and immunogenicity, almost chemical inertness (distinctly from their inherent catalytic properties), while silver nanomaterials present intrinsic antimicrobial activity against a broad spectrum of microorganisms and related MDR infections (e.g., towards Gram(−) and Gram(+) mature biofilms of MRSA), and disruption of biofilm formations while being safe for mammalian cells [124][125][126].Ultimately, both Au and Ag NPs share nano features specific to noble metal systems, i.e., localized surface plasmon resonance (LSPR, arising from their resonant oscillation of their free electrons upon light exposure) and resonance energy transfer (RET), with subsequent optical and photothermal properties of enhancing appositeness in aPDT applications and PDI efficacy (e.g., ROS production) [127][128][129]. For the most part, Au and Ag NPs of various shapes (e.g., spheres, rods, cubes) are combined with organic PS molecules such as RB and MB [128][129][130][131][132][133][134][135][136], but also with metallated PSs such as ruthenium complexes, metallophthalocyanines, and metalloporphyrins [108,137,138]; the corresponding PS nanovehicles can also be labeled as "conjugates" but they strictly differ from the "mixtures" involving metal NPs and PS molecules [139]. Other noble metal NPs, viz., platinum, have also been employed in aPDT applications due to their multitarget action to inactivate microbes, although to a lower degree up to now owing to synthetic limitations [27,140].…”

Plasmonic photoreactors-coated plastic tubing as combined-active-and-passive antimicrobial flow sterilizer

“…30,50 The produced ROS increases the permeability of the membrane around the Ag NP, exposes the Ag NPs to the ambient medium, and triggers a concomitant release of both [Ru(bpy) 3 ] 2+ and Ag + ions. Both species are known to be bactericidal, 39,51 and can interact synergistically to create a strong light-mediated antibacterial effect. The plasmonic photoreactor strategy was demonstrated to reduce the concentration of Gram-positive Arthrobacter sp.…”

Identification of ruthenium (II) complexes with furan‐substituted ligands as possible antibacterial agents against Staphylococcus aureus

“…Recently years, transition metal-based compounds explored as antimicrobials or adjuvants to existing antibiotics were received widely attention (Frei et al, 2020;Pisani et al, 2010;Wareham et al, 2015). It worthy to noted that many ruthenium-based complexes have displayed significant antimicrobial activity (Ghosh et al, 2021;Jain et al, 2021;Li et al, 2015;Pandrala et al, 2013;Yang et al, 2018). Up to now, there exist over 200 scientific literatures on the antimicrobial activity of various ruthenium-based compounds.…”