Insights into the Mechanism of Action of Bactericidal Lipophosphonoxins

0456130 - MBÚ 2016 RIV US eng J - Journal Article
Panova, Natalya - Zborníková, E. - Šimák, O. - Pohl, R. - Kolář, M. - Bogdanová, K. - Večeřová, R. - Seydlová, G. - Fišer, R. - Hadravová, R. - Šanderová, Hana - Vítovská, Dragana - Šiková, Michaela - Látal, T. - Lovecká, P. - Barvík, I. - Krásný, Libor - Rejman, D.
Insights into the Mechanism of Action of Bactericidal Lipophosphonoxins.
PLoS ONE. Roč. 10, č. 12 (2015). ISSN 1932-6203. E-ISSN 1932-6203
R&D Projects: GA TA ČR TA02010035; GA ČR(CZ) GBP305/12/G034
Institutional support: RVO:61388971
Keywords : CATIONIC STEROID ANTIBIOTICS * BACILLUS-SUBTILIS * ANTIBACTERIAL PROPERTIES
Subject RIV: CE - Biochemistry
Impact factor: 3.057, year: 2015

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.
Permanent Link: http://hdl.handle.net/11104/0256700