Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 14, Pages 6098-6118Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00355
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Funding
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Science
- Ministry of Education, Youth and Sports of the Czech Republic at the CZ-OPENSCREEN: National infrastructure for chemical biology [LO1220, LM2015063]
- Czech Science Foundation [P305/12/G034]
- Czech research infrastructure for systems biology C4SYS [LM2015055]
- Czech ministry of health [17-29680A, IGA_LF_2016_022]
- GAUK [186855, 794317]
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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.
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