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.

Department of Analytical Chemistry Faculty of Science Charles University Albertov 6 128 43 Prague 2 Czech Republic

Department of Genetics and Microbiology Faculty of Science Charles University Viničná 5 128 43 Prague 2 Czech Republic

Department of Microbiology Faculty of Medicine and Dentistry Palacký University Olomouc Hněvotínská 3 775 15 Olomouc Czech Republic

Institute of Microbiology Czech Academy of Sciences v v i Vídeňská 1083 142 20 Prague 4 Czech Republic

Institute of Molecular Genetics Czech Academy of Sciences v v i Vídeňská 1083 142 20 Prague 4 Czech Republic

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences v v i Flemingovo nám 2 166 10 Prague 6 Czech Republic

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