Membrane-targeting peptides enhancing uptake of ruthenium(II) polypyridyl photosensitiser into clinically relevant bacteria Ng Xiao Ying 1 , Fong Kar Wai 1 , Mohamedali Elhag Mohamed Ahmed 4 , Bong Wan Qing 4 , Kiew Lik Voon 3 , Katrina Chung Pooi Yin 5 , Liew Yun Khoon 7 , Cheong Siew Lee 2 , Mohd Zulkefeli 2 , Low May Lee 6 1 School of Postgraduate Studies, International Medical University (IMU), Malaysia, 2 Department of Pharmaceutical Chemistry, School of Pharmacy, IMU, Malaysia, 3 Department of Pharmacology, Faculty of Medicine, Universiti Malaya, Malaysia, 4 School of Pharmacy, IMU, Malaysia, 5 Department of Microbiology, School of Medicine, IMU, Malaysia, 6 Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, UCSI University, Malaysia, 7 Department of Life Sciences, School of Pharmacy, IMU, Malaysia Introduction: In recent years, photodynamic therapy (PDT) has emerged as potential alternative in combating the growing threat of global antibiotic resistance 1-2 . In PDT, free radicals are generated in the presence of photosensitisers and oxygen under light irradiation of a specific wavelength, causing cytotoxic damage to bacteria 3 . Ruthenium(II) photosensitisers (Ru-PS) are focused in our work because some Ru(II) complexes possessing rich photochemical properties and additional advantages have shown excellent antibacterial activities in previous studies 4-5 . However, they may experience low bacterial uptake when administered in vivo . Hence, the objective of this study is to investigate the potential of bacterial membrane-targeting peptides - arginine- tryptophan (Arg-Trp) in enhancing bacterial uptake of the Ru-PS. Methods: Minimum inhibitory concentrations (MIC) of synthesised and characterised Ru(II) complex and Arg-Trp peptides ranging from 0.125-128 µM against eight bacteria, including Staphylococcus aureus (SA), Acinetobacter baumannii (AB), Pseudomonas aeruginosa (PA) and Escherichia coli (EC), both susceptible (S) and resistant (R) strains, were determined using broth microdilution method. Combination assays using a 1:1 ratio of Ru(II) complex and respective peptides were carried out and fractional inhibitory concentration indexes (FICI) were calculated. Molecular docking studies were performed using the Glide program of the Schrödinger Suite to study in silico effect of efflux pumps on Ru(II) complex. Results: Ru(II) complex demonstrated promising MIC values only when tested against SA, whereby the MIC results were correlated to the molecular docking score. Interestingly, combination of Ru(II) complex with RW8 or RW9 respectively, showed synergistic and/or additive effects against SA, EC(S) and AB(R), with or without irradiation. Conclusion: Arg-Trp peptides enhanced the antibacterial activities of Ru(II) complex. References 1. Cieplik, F., Deng, D., Crielaard, W., Buchalla, W., Hellwig, E., Al-Ahmad, A., Maisch, T., Crit. Rev. Microbiol. 2018 , 44(5), 571-589. 2. Hynek, J., Zelenka, J., Rathouský, J., Kubát, P., Ruml, T., Demel, J., Lang, K., ACS Appl Mater Interfaces. 2018 , 10(10), 8527–8535. 3. Lin, J., Li, J., Gopal, A., Munshi, T., Chu, Y., Wang, J., Liu, T., Shi, B., Chen, X., Yan, L., Chem comm. 2019 , 55, 2656-2659. 4. Sur, V.P., Mazumdar, A., Kopel, P., Mukherjee, S., Vítek, P., Michalkova, H., Vaculoviˇcová1, M., Moulick, A., Int. J. Mol. Sci. 2020 , 21, 2656. 5. Frei, A., Zuegg, J., Elliott, A.G., Baker, M., Braese, S., Brown, C., Chen, F., Dowson, C.G., Dujardin, G., Jung, N., King, A.P., Mansour, A.M., Massi, M., Moat, J., Mohamed, H.A., Renfrew, A.K., Rutledge, P.J., Sadler, P.J., Todd, M.H., Willans, C.E., Wilson, J.J., Cooper, M.A., Blaskovich, M.A.T., Chem. Sci. 2020 , 11, 2627.
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