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In vitro and in vivo photodynamic efficacies of novel and conventional phenothiazinium photosensitizers against multidrug-resistant Candida auris

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Abstract

The fast-emerging and multidrug-resistant Candida auris is the first fungal pathogen to be considered a threat to global public health. Thus, there is a high unmet medical need to develop new therapeutic strategies to control this species. Antimicrobial photodynamic therapy (APDT) is a promising alternative that simultaneously targets and damages numerous microbial biomolecules. Here, we investigated the in vitro and in vivo effects of APDT with four phenothiazinium photosensitizers: (i) methylene blue (MB), (ii) toluidine blue (TBO), and two MB derivatives, (iii) new methylene blue (NMBN) and (iv) the pentacyclic derivative S137, against C. auris. To measure the in vitro efficacy of each PS, minimal inhibitory concentrations (MICs) and survival fraction were determined. Also, the efficiency of APDT was evaluated in vivo with the Galleria mellonella insect model for infection and treatment. Although the C. auris strain used in our study was shown to be resistant to the most-commonly used clinical antifungals, it could not withstand the damages imposed by APDT with any of the four photosensitizers. However, for the in vivo model, only APDT performed with S137 allowed survival of infected G. mellonella larvae. Our results show that structural and chemical properties of the photosensitizers play a major role on the outcomes of in vivo APDT and underscore the need to synthesize and develop novel photosensitizing molecules against multidrug-resistant microorganisms.

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Funding

This research was funded by Fundação de Amparo à Pesquisa do Estado de São Paulo—Brazil (FAPESP), grant number 2017/25300-8 and 2020/07546-2. P.H.G.B., scholarship financed by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brazil (CAPES)—Finance Code 001. G.T.P.B. would like to thank the National Council for Scientific and Technological Development for a post-doctoral fellowship (165191/2020–1). GULB and MRVZK would like to thank the National Council for Scientific and Technological Development for the research productivity fellowship 312640/2021-8 and 310425/2021-2, respectively.

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“Conceptualization: MRVZK, GULB, MW, and EN; methodology: PHGB, and LT; software: LT; validation PHGB and LT; formal analysis: MRVZK, PHGB, and LT; investigation: MRVZK, PHGB, LT, EN, and GTPB; resources: MRVZK; data curation: MRVZK; writing—original draft preparation: MRVZK; writing—review and editing: PHGB, LT, EN, GULB, GTPB, and MW; supervision: MRVZK; project administration: MRVZK; funding acquisition, MRVZK. All authors have read and agreed to the published version of the manuscript.”

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Correspondence to Marcia Regina von Zeska Kress.

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Grizante Barião, P.H., Tonani, L., Brancini, G.T.P. et al. In vitro and in vivo photodynamic efficacies of novel and conventional phenothiazinium photosensitizers against multidrug-resistant Candida auris. Photochem Photobiol Sci 21, 1807–1818 (2022). https://doi.org/10.1007/s43630-022-00258-4

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