AUTHOR=Batishchev Oleg V. , Kalutskii Maksim A. , Varlamova Ekaterina A. , Konstantinova Anna N. , Makrinsky Kirill I. , Ermakov Yury A. , Meshkov Ivan N. , Sokolov Valerij S. , Gorbunova Yulia G. 

TITLE=Antimicrobial activity of photosensitizers: arrangement in bacterial membrane matters

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=10

YEAR=2023

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2023.1192794

DOI=10.3389/fmolb.2023.1192794

ISSN=2296-889X

ABSTRACT=<p>Porphyrins are well-known photosensitizers (PSs) for antibacterial photodynamic therapy (aPDT), which is still an underestimated antibiotic-free method to kill bacteria, viruses, and fungi. In the present work, we developed a comprehensive tool for predicting the structure and assessment of the photodynamic efficacy of PS molecules for their application in aPDT. We checked it on a series of water-soluble phosphorus(V) porphyrin molecules with OH or ethoxy axial ligands and phenyl/pyridyl peripheral substituents. First, we used biophysical approaches to show the effect of PSs on membrane structure and their photodynamic activity in the lipid environment. Second, we developed a force field for studying phosphorus(V) porphyrins and performed all-atom molecular dynamics simulations of their interactions with bacterial lipid membranes. Finally, we obtained the structure-activity relationship for the antimicrobial activity of PSs and tested our predictions on two models of Gram-negative bacteria, <italic>Escherichia coli</italic> and <italic>Acinetobacter baumannii</italic>. Our approach allowed us to propose a new PS molecule, whose MIC<sub>50</sub> values after an extremely low light dose of 5 J/cm<sup>2</sup> (5.0 ± 0.4 μg/mL for <italic>E. coli</italic> and 4.9 ± 0.8 μg/mL for <italic>A. baumannii</italic>) exceeded those for common antibiotics, making it a prospective antimicrobial agent.</p>