4 years ago

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

Lipophosphonoxins II: Design, Synthesis, and Properties of Novel Broad Spectrum Antibacterial Agents
Radek Pohl, Petr Bartůněk, Dominik Rejman, Renata Večeřová, Marcel Ehn, Hana Šanderová, Radovan Fišer, Milan Kolář, David Sedlák, Eva Zborníková, Gabriela Seydlová, Libor Krásný, Tomáš Křížek, Ondřej Šimák, Jiří Pospíšil, Dragana Vítovská, Petra Sudzinová, Kateřina Bogdanová, Oldřich Benada, Natalya Panova
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 demonstrate 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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00355

DOI: 10.1021/acs.jmedchem.7b00355

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