LEGO-Lipophosphonoxins: A Novel Approach in Designing Membrane Targeting Antimicrobials.

Autor:	Do Pham DD; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences v.v.i., Flemingovo nám. 2, 166 10 Prague 6, Czech Republic., Mojr V; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences v.v.i., Flemingovo nám. 2, 166 10 Prague 6, Czech Republic., Helusová M; Department of Genetics and Microbiology, Faculty of Science, Charles University, Viničná 5, 128 43 Prague 2, Czech Republic., Mikušová G; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences v.v.i., Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.; Department of Genetics and Microbiology, Faculty of Science, Charles University, Viničná 5, 128 43 Prague 2, Czech Republic., Pohl R; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences v.v.i., Flemingovo nám. 2, 166 10 Prague 6, Czech Republic., Dávidová E; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences v.v.i., Flemingovo nám. 2, 166 10 Prague 6, Czech Republic., Šanderová H; Institute of Microbiology, Czech Academy of Sciences v.v.i., Vídečská 1083, 142 20 Prague 4, Czech Republic., Vítovská D; Institute of Microbiology, Czech Academy of Sciences v.v.i., Vídečská 1083, 142 20 Prague 4, Czech Republic., Bogdanová K; Department of Microbiology, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 3, 775 15 Olomouc, Czech Republic., Večeřová R; Department of Microbiology, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 3, 775 15 Olomouc, Czech Republic., Sedláková MH; Department of Microbiology, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 3, 775 15 Olomouc, Czech Republic., Fišer R; Department of Genetics and Microbiology, Faculty of Science, Charles University, Viničná 5, 128 43 Prague 2, Czech Republic., Sudzinová P; Institute of Microbiology, Czech Academy of Sciences v.v.i., Vídečská 1083, 142 20 Prague 4, Czech Republic., Pospíšil J; Institute of Microbiology, Czech Academy of Sciences v.v.i., Vídečská 1083, 142 20 Prague 4, Czech Republic., Benada O; Institute of Microbiology, Czech Academy of Sciences v.v.i., Vídečská 1083, 142 20 Prague 4, Czech Republic., Křížek T; Department of Analytical Chemistry, Faculty of Science, Charles University, Albertov 6, 128 43 Prague 2, Czech Republic., Galandáková A; Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 3, 775 15 Olomouc, Czech Republic., Kolář M; Department of Microbiology, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 3, 775 15 Olomouc, Czech Republic., Krásný L; Institute of Microbiology, Czech Academy of Sciences v.v.i., Vídečská 1083, 142 20 Prague 4, Czech Republic., Rejman D; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences v.v.i., Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2022 Jul 28; Vol. 65 (14), pp. 10045-10078. Date of Electronic Publication: 2022 Jul 15.
DOI:	10.1021/acs.jmedchem.2c00684
Abstrakt:	The alarming rise of bacterial antibiotic resistance requires the development of new compounds. Such compounds, lipophosphonoxins (LPPOs), were previously reported to be active against numerous bacterial species, but serum albumins abolished their activity. Here we describe the synthesis and evaluation of novel antibacterial compounds termed LEGO-LPPOs, loosely based on LPPOs, consisting of a central linker module with two attached connector modules on either side. The connector modules are then decorated with polar and hydrophobic modules. We performed an extensive structure-activity relationship study by varying the length of the linker and hydrophobic modules. The best compounds were active against both Gram-negative and Gram-positive species including multiresistant strains and persisters. LEGO-LPPOs act by first depleting the membrane potential and then creating pores in the cytoplasmic membrane. Importantly, their efficacy is not affected by the presence of serum albumins. Low cytotoxicity and low propensity for resistance development demonstrate their potential for therapeutic use.
Databáze:	MEDLINE
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