Ruthenium(II) polypyridyl complexes (RPCs) are gaining
momentum
in photoactivated chemotherapy (PACT), thanks to the possibility of
overcoming the classical reliance on molecular oxygen of photodynamic
therapy while preserving the selective drug activation by using light.
However, notwithstanding the intriguing perspectives, the translation
of such an approach in the development of new antimicrobials has been
only barely considered. Herein, MTZH-1 and MTZH-2, two novel analogues
of metronidazole (MTZ), a mainstay drug in the treatment of anaerobic
bacterial infections, were designed and inserted in the strained ruthenium
complexes [Ru(tpy)(dmp)(MTZ-1)]PF6 (Ru2) and
[Ru(tpy)(dmp)(MTZ-2)]PF6 (Ru3) (tpy = terpyridine,
dmp = 2,9-dimethyl-1,10-phenanthroline) (Chart 1). Analogously to
the parental compound [Ru(tpy)(dmp)(5NIM)]PF6 (Ru1) (5-nitroimidazolate), the Ru(II)-imidazolate coordination of MTZ
derivatives resulted in promising Ru(II) photocages, capable to easily
unleash the bioactive ligands upon light irradiation and increase
the antibacterial activity against Bacillus subtilis, which was chosen as a model of Gram-positive bacteria. The photoreleased
5-nitroimidazole-based ligands led to remarkable phototoxicities under
hypoxic conditions (<1% O2), with the lead compound Ru3 that exhibited the highest potency across the series,
being comparable to the one of the clinical drug MTZ. Besides, the
chemical architectures of MTZ derivatives made their interaction with
NimAunfavorable, being NimA a model of reductases responsible for
bacterial resistance against 5-nitroimidazole-based antibiotics, thus
hinting at their possible use to combat antimicrobial resistance.
This work may therefore provide fundamental knowledge in the design
of novel photoresponsive tools to be used in the fight against infectious
diseases. For the first time, the effectiveness of the “photorelease antimicrobial therapy” under therapeutically
relevant hypoxic conditions was demonstrated.