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Insights into the Mechanism of Action of Bactericidal Lipophosphonoxins
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 lipophospho...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696656/ https://www.ncbi.nlm.nih.gov/pubmed/26716439 http://dx.doi.org/10.1371/journal.pone.0145918 |
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author | Panova, Natalya Zborníková, Eva Šimák, Ondřej Pohl, Radek Kolář, Milan Bogdanová, Kateřina Večeřová, Renata Seydlová, Gabriela Fišer, Radovan Hadravová, Romana Šanderová, Hana Vítovská, Dragana Šiková, Michaela Látal, Tomáš Lovecká, Petra Barvík, Ivan Krásný, Libor Rejman, Dominik |
author_facet | Panova, Natalya Zborníková, Eva Šimák, Ondřej Pohl, Radek Kolář, Milan Bogdanová, Kateřina Večeřová, Renata Seydlová, Gabriela Fišer, Radovan Hadravová, Romana Šanderová, Hana Vítovská, Dragana Šiková, Michaela Látal, Tomáš Lovecká, Petra Barvík, Ivan Krásný, Libor Rejman, Dominik |
author_sort | Panova, Natalya |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4696656 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-46966562016-01-13 Insights into the Mechanism of Action of Bactericidal Lipophosphonoxins Panova, Natalya Zborníková, Eva Šimák, Ondřej Pohl, Radek Kolář, Milan Bogdanová, Kateřina Večeřová, Renata Seydlová, Gabriela Fišer, Radovan Hadravová, Romana Šanderová, Hana Vítovská, Dragana Šiková, Michaela Látal, Tomáš Lovecká, Petra Barvík, Ivan Krásný, Libor Rejman, Dominik PLoS One Research Article 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. Public Library of Science 2015-12-30 /pmc/articles/PMC4696656/ /pubmed/26716439 http://dx.doi.org/10.1371/journal.pone.0145918 Text en © 2015 Panova et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Panova, Natalya Zborníková, Eva Šimák, Ondřej Pohl, Radek Kolář, Milan Bogdanová, Kateřina Večeřová, Renata Seydlová, Gabriela Fišer, Radovan Hadravová, Romana Šanderová, Hana Vítovská, Dragana Šiková, Michaela Látal, Tomáš Lovecká, Petra Barvík, Ivan Krásný, Libor Rejman, Dominik Insights into the Mechanism of Action of Bactericidal Lipophosphonoxins |
title | Insights into the Mechanism of Action of Bactericidal Lipophosphonoxins |
title_full | Insights into the Mechanism of Action of Bactericidal Lipophosphonoxins |
title_fullStr | Insights into the Mechanism of Action of Bactericidal Lipophosphonoxins |
title_full_unstemmed | Insights into the Mechanism of Action of Bactericidal Lipophosphonoxins |
title_short | Insights into the Mechanism of Action of Bactericidal Lipophosphonoxins |
title_sort | insights into the mechanism of action of bactericidal lipophosphonoxins |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696656/ https://www.ncbi.nlm.nih.gov/pubmed/26716439 http://dx.doi.org/10.1371/journal.pone.0145918 |
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