Synergistic effect of combined imipenem and photodynamic treatment with the cationic Ir(III) complexes to polypyridine ligand on carbapenem-resistant Klebsiella pneumoniae.

Abstract

Carbapenemase-producing strains of Klebsiella pneumoniae (KPC+) are one of the multi-drug resistant bacteria with the highest risk for human health. The colistin is the only antibiotic option against KPC+; however, due to its emerging resistance, therapies such as antimicrobial photodynamic inactivation (aPDI), are needed. APDI uses photosensitizer compounds (PS) to produce light-activated local oxidative stress (photooxidative stress). Within the PSs variety, cationic PSs are thought to interact closely with the bacterial envelope producing an increased cytotoxic effect. The Ir(III)-based cationic compounds, PSIR-3, and PSIR-4 were tested on aPDI and compared to a positive control of Ru(II)-based PS. The PSIR-3 and PSIR-4 abilities to inhibit the growth of KPC+ and KPC- bacteria were evaluated, under 17 μW/cm2 photon flux. Also, the cytotoxicity of the PSs in eukaryotic cells was determined by MTS and trypan blue exclusion assays. After light-activation, only the PSIR-3 compound inhibited 3 log10 (> 99.9 %) bacterial growth in a minimum dose of 4 μg/mL with the lethality of 30 min of light exposure. Outstandingly, the compound PSIR-3 showed a synergistic effect with imipenem, significantly increasing the bacterial inhibition of KPC+ to 6 log10, which was not observed in the control compound. In normal immortalized gastric cell line GES-1, the compound PSIR-3 showed no significant cytotoxicity, although increased cytotoxicity under light-activation was observed on gastric cancer-derived cells AGS. The PSIR-3 compound produces an efficient aPDI, killing K. pneumoniae KPC+- strains, and increasing its susceptibility in conjunction with imipenem, exhibiting low cytotoxicity to normal eukaryotic cells.