Lipophosphonoxins II: Design, Synthesis, and Properties of Novel Broad Spectrum Antibacterial Agents

0477671 - ÚOCHB 2018 RIV US eng J - Journal Article
Seydlová, G. - Pohl, Radek - Zborníková, Eva - Ehn, Marcel - Šimák, Ondřej - Panova, Natalya - Kolář, M. - Bogdanová, K. - Večeřová, R. - Fišer, R. - Šanderová, Hana - Vítovská, Dragana - Sudzinová, Petra - Pospíšil, Jiří - Benada, Oldřich - Křížek, T. - Sedlák, David - Bartůněk, Petr - Krásný, Libor - Rejman, Dominik
Lipophosphonoxins II: Design, Synthesis, and Properties of Novel Broad Spectrum Antibacterial Agents.
Journal of Medicinal Chemistry. Roč. 60, č. 14 (2017), s. 6098-6118. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA MŠMT LO1220; GA MŠMT LM2015063; GA ČR(CZ) GBP305/12/G034; GA MŠMT(CZ) LM2015055; GA MZd(CZ) NV17-29680A
Institutional support: RVO:61388963 ; RVO:61388971 ; RVO:68378050
Keywords : resistant Staphylococcus aureus * cationic steroid antibiotics * antimicrobial peptides
OECD category: Microbiology; Microbiology (MBU-M)
Impact factor: 6.253, year: 2017

The increase in the number of bacterial strains resistant to known antibiotics is alarming. In this study we report the synthesis of novel compounds termed Lipophosphonoxins II (LPPO II). We show that LPPO II display excellent activities against Gram-positive and-negative bacteria, including pathogens and multiresistant strains. We describe their mechanism of action plasmatic membrane pore-forming activity selective for bacteria. Importantly, LPPO II neither damage nor cross the eukaryotic plasmatic membrane at their bactericidal concentrations. Further, we LPPO II have low propensity for resistance development, likely due to their rapid membrane-targeting mode of action. Finally, we reveal that LPPO II are not toxic to either eukaryotic cells or model animals when administered orally or topically. Collectively, these results suggest that LPPO II are highly promising compounds for development into pharmaceuticals.
Permanent Link: http://hdl.handle.net/11104/0273963