Ruthenium(II) Polypyridyl Complexes as Photosensitizers for Antibacterial Photodynamic Therapy: A Structure–Activity Study on Clinical Bacterial Strains

Abstract

As a growing public health concern, the worldwide spread of antimicrobial resistance urges the development of new therapies. Antibacterial photodynamic therapy (a-PDT) may be an alternative to conventional antibiotic therapy. Herein we report the synthesis and characterization of seven original reactive oxygen species (ROS)-producing ruthenium(II) polypyridyl complexes. These are part of a collection of 17 derivatives varying in terms of the nature of the substituent(s), molecular symmetry, electrical charge, and counterions. They were characterized by considering 1) their physical properties (absorption coefficient at irradiation wavelength, O generation quantum yield, luminescence) and 2) their antibacterial activity in a series of photodynamic assays using Gram-positive and Gram-negative bacteria of clinical relevance. The results unveiled some structure-activity relationships: one derivative that combines multiple beneficial features for a-PDT was effective against all the bacteria considered, regardless of their Gram status, species, or antibiotic resistance profile. This systematic study could guide the design of next-generation ruthenium-based complexes for enhanced antibacterial photodynamic strategies.

Metal Complexes, an Untapped Source of Antibiotic Potential?

“…However, 10 showed activity against both normal lung fibroblasts (MRC-5, IC 50 = 15.6 µM) and human cervical carcinoma cells (HeLa, IC 50 = 5.7 µM) after 48 h of incubation in the dark (11 was nontoxic up to 100 µM in the absence of light). More recently, Le Gall et al, reported a structure-activity relationship of 17 different light-activated ruthenium complexes (12 is shown as an illustrative example, Figure 5) with a range of activity profiles against various Gram(+) and Gram(−) strains (12 led to a 5 log reduction in growth in both S. aureus RN4220 and MRSA N315) [80]. In 2019 Feng et al, described a series of charged ruthenium complexes that showed good activity against S. aureus and MRSA upon light irradiation (only minor activity against Gram(−) E. coli was found).…”

Recent Considerations in the Application of RAPTA‐C for Cancer Treatment and Perspectives for Its Combination with Immunotherapies

“…Indeed, the tumor microenvironment including, for example, several biochemical modulating molecules, redox species, different cell types or nutrients, strongly influences treatment responses to chemotherapies and, importantly, the tumor microenvironment and tumor treatment can impact on an immune response. [61] Ru(II) polypyridyl complexes can be reorganized by adding substituents that enhance the light absorption properties [62] that improve their activity. [51,52] KP1019 was initially evaluated on eight patients with solid tumors, applied intravenously to estimate dose escalation with concentrations ranging from 25-600 mg given twice a week over a 3-week period.…”

“…[38,43,55] In 2011, a phase I dose escalation study for (N)KP1339 was initiated, including 16 patients with solid tumors that received one of six doses following a certain treatment schedule. [60,62,63] Although yet to enter clinical trials, a series of experimental drugs [66][67][68][69] that have been extensively evaluated in pre-clinical models are the so-called RAPTA compounds, with the general formula [Ru(arene)Cl 2 PTA] ( Figure 1). It should be noted that concentrations >400 mg induce a transient green discoloration of the patients' plasma.…”

“…It should be noted that concentrations >400 mg induce a transient green discoloration of the patients' plasma. [34,43,61,62] Notably, the biological properties of RAPTA compounds can be modulated in a systematic way by manipulating the groups attached to the arene ring. [55][56][57][58] The activity of selected Ru(II) polypyridyl complexes is superior to that of some PS in clinical use, for example, antimicrobial agents as porfimer sodium or 5-aminolevulinic acid.…”

Anticancer Photodynamic Therapy Using Ruthenium(II) and Os(II)-Based Complexes as Photosensitizers

“…Historically, Pt(IV)-, Ru(II)-, and Rh(III)-based complexes were most actively studied as PSs followed by Ir(III) and Os(II) complexes; see the review by Monro et al [5]. The examples of the most recent studies [22][23][24][25][26] include a summary on the use of ruthenium complexes as PSs in PDT [27].This chapter reviews the results obtained by our group and collaborators. The properties and PDT efficacy of Theralase Technologies Inc. PSs [28] and Ru(II)-and Os(II)-based complexes are discussed in the perspective of their clinical application.…”