Synergistic antibacterial photodynamic activity of ruthenium(ii) complexes with polymyxin b/efflux inhibitor (PAβN) against clinically relevant bacteria Fong Kar Wai 1 , Ng Xiao Ying 1 , Mohamedali Elhag Mohamed Ahmed 2 , Bong Wan Qing 2 , Prof. Dr. Mohd Zulkefeli bin Mat Jusoh 2 , A/P. Dr. Kiew Lik Voon 3 , Dr. Katrina Chung Pooi Yin 2 , Dr. Liew Yun Khoon 2 , Dr. Cheong Siew Lee 2, Dr. Low May Lee 4 1 School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia, 2 School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia; 3 Department of Pharmacology, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia, 4 Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia Introduction/Background: In recent years, photodynamic therapy (PDT) has emerged as potential alternatives in combating the growing threat of global antibiotic resistance. In PDT, free radicals are generated in the presence of photosensitizers and oxygen under light irradiation of specific wavelength, causing cytotoxic damage to bacteria. The objective of this study is to investigate the potential of synthesized ruthenium, Ru(II) complexes as antibacterial photosensitizers and antibiotic adjuvants. Methodology: Minimum inhibitory concentrations (MIC) of synthesized and characterized Ru(II) complexes ranging from 0.125-128 µM against Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA) were determined using broth microdilution method. A checkerboard method was used to generate combinations of Ru(II) complexes with polymyxin B sulfate (PMX) and phenylalanine-arginine beta-naphthylamide (PAβN), respectively against susceptible (S) and resistant (R) strains of bacteria. Molecular docking studies was performed using Glide program of Schrödinger Suite to study the effect of efflux pumps on Ru(II) complexes. Results: Both Complex 1 and Complex 2 demonstrated promising MIC values when tested against SA. Interestingly, Complex 2 showed additional activities against PA (R). Combination of Complex 1 or Complex 2 with PMX showed synergistic and additive effects against PA (R) upon irradiation. Similar effects upon irradiation were observed as well when combining both compounds with PAβN respectively, against SA. The interactions found from molecular docking investigation between both ruthenium(II) complexes and NorA, a multidrug efflux transporter of SA as well as AcrB of PA will be discussed. Conclusions: Complex 1 and Complex 2 showed antibacterial photodynamic activities against SA (S), SA (R) 1. Gan W.K., Liew H.S., Pua L.J.W., Ng X.Y., Fong K.W., Cheong S.L., Liew Y.K. and Low M.L. (2022). Novel Cu(II) Schiff base complex combination with polymyxin B/phenylalanine-arginine β-naphthylamide against various bacterial strains. International Journal of Peptide Research and Therapeutics, 28, 60. 2. Scorzoni L., Sangalli-Leite F., Singulani J.de L., e Silva A.C.A.de P., Costa-Orlandi C.B., Fusco-Almeida A.M., Mendes- Giannini M.J.S. (2016). Searching new antifungals: The use of in vitro and in vivo methods for evaluation of natural compounds. Journal of Microbiological Methods, 123, 68-78. 3. Low M.L., Paulus G., Dorlet P., Guillot R., Rosli R., Delsuc N., Crouse K.A. and Policar C. (2015). Synthesis, characterization and biological activity of Cu (II), Zn (II) and Re(I) complexes derived from S-benzyldithiocarbazate and 3-acetylcoumarin. BioMetals, 28(3), 553-566. 4. Jain A., Winkel B.S. and Brewer K. J. (2022). Photodynamic antimicrobial studies on a Ruthenium-based metal complex. Inorganica Chimica Acta, 538, 120996. and PA (R). References
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