TY - DATA T1 - Insights into the Mechanism of Action of Bactericidal Lipophosphonoxins PY - 2016/01/05 AU - Natalya Panova AU - Eva Zborníková AU - Ondřej Šimák AU - Radek Pohl AU - Milan Kolar AU - Katerina Bogdanova AU - Renata Vecerova AU - Gabriela Seydlová AU - Radovan Fiser AU - Romana Hadravová AU - Hana Šanderová AU - Dragana Vítovská AU - Michaela Šiková AU - Tomáš Látal AU - Petra Lovecká AU - Ivan Barvík AU - Libor Krásný AU - Dominik Rejman UR - https://plos.figshare.com/articles/dataset/_Insights_into_the_Mechanism_of_Action_of_Bactericidal_Lipophosphonoxins_/1630226 DO - 10.1371/journal.pone.0145918 L4 - https://ndownloader.figshare.com/files/2616751 L4 - https://ndownloader.figshare.com/files/2616752 L4 - https://ndownloader.figshare.com/files/2616753 L4 - https://ndownloader.figshare.com/files/2616754 L4 - https://ndownloader.figshare.com/files/2616756 L4 - https://ndownloader.figshare.com/files/2616757 L4 - https://ndownloader.figshare.com/files/2616758 L4 - https://ndownloader.figshare.com/files/2616759 L4 - https://ndownloader.figshare.com/files/2616760 L4 - https://ndownloader.figshare.com/files/2616761 KW - strain KW - transepithelial transport KW - Bactericidal Lipophosphonoxins KW - cell disintegration KW - Ames test KW - bactericidal concentrations LPPOs KW - compound KW - plasmatic membrane KW - acidic environment N2 - The advantages offered by established antibiotics in the treatment of infectious diseases are endangered due to the increase in the number of antibiotic-resistant bacterial strains. This leads to a need for new antibacterial compounds. Recently, we discovered a series of compounds termed lipophosphonoxins (LPPOs) that exhibit selective cytotoxicity towards Gram-positive bacteria that include pathogens and resistant strains. For further development of these compounds, it was necessary to identify the mechanism of their action and characterize their interaction with eukaryotic cells/organisms in more detail. Here, we show that at their bactericidal concentrations LPPOs localize to the plasmatic membrane in bacteria but not in eukaryotes. In an in vitro system we demonstrate that LPPOs create pores in the membrane. This provides an explanation of their action in vivo where they cause serious damage of the cellular membrane, efflux of the cytosol, and cell disintegration. Further, we show that (i) LPPOs are not genotoxic as determined by the Ames test, (ii) do not cross a monolayer of Caco-2 cells, suggesting they are unable of transepithelial transport, (iii) are well tolerated by living mice when administered orally but not peritoneally, and (iv) are stable at low pH, indicating they could survive the acidic environment in the stomach. Finally, using one of the most potent LPPOs, we attempted and failed to select resistant strains against this compound while we were able to readily select resistant strains against a known antibiotic, rifampicin. In summary, LPPOs represent a new class of compounds with a potential for development as antibacterial agents for topical applications and perhaps also for treatment of gastrointestinal infections. ER -