Synthesis and antibacterial activity of the second generation LEGO-LPPO

Kód výsledku v IS VaVaI

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Výsledek na webu

<a href="http://www.ccsss.cz/index.php/ccsss/issue/view/52/92" target="_blank" >http://www.ccsss.cz/index.php/ccsss/issue/view/52/92</a>

DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Synthesis and antibacterial activity of the second generation LEGO-LPPO

Popis výsledku v původním jazyce

Bacterial pathogens resistant to antibiotics (ATB) are becoming an increasingly serious global problem. Current ATB targeting bacterial biosynthetic processes are facing emerging resistant strains. An attractive target for the development of antibacterial compounds is the cytoplasmic membrane as the composition of bacterial and mammalian cell membranes differs, resulting in different biophysical properties. In contrast to majority of classical antibiotics requiring metabolically active bacterial cells, membrane targeting antimicrobials are capable of also killing persistent (dormant) bacteria. Antimicrobial peptides (AMP) and host defense peptides (HDP) are examples of membrane-active compounds that represent the first line of defense in many multicellular organisms and possess a broad range of biological activities. However, their clinical usage is limited by their in vivo toxicity, stability, limited bioavailability, and large production costs. We are developing lipophosphonoxins (LPPO) – antimicrobial compounds belonging to the class of small molecule membrane targeting agents (SMMTA). Their general structure consists of four modules: a nucleoside module (NM), a polar module (PM), a hydrophobic module (HM), and a phosphonate connector module (CM). The first generation LPPO (LPPO I) demonstrated excellent bactericidal activity against various Gram-positive species. We have shown that at their bactericidal concentrations, LPPO act via the disruption of the cytoplasmic membrane. The second-generation LPPO (LPPO II) have redesigned PM to bear more polar charges. LPPO II increased their efficacy to Gram-positive and extended bactericidal activity to Gram negative bacteria. Their antibacterial activity, however, is abolished in the presence of serum albumins. By introducing LEGO-LPPO (Linker-Evolved-Group Optimized-LPPO), modular configuration was modified to include two LPPO units symmetrically attached by CM at the ends of linker module (LM), NM was omitted. Redesign of molecular skeleton brought improvements in antimicrobial activity and eliminated interactions with serum albumins. Because of chiral nature of phosphorus atoms in the connector modules the first generation LEGO-LPPO molecules are isolated as a mixture of three diastereoisomers. Here we present design and synthesis of new generation LEGO-LPPO-II based on connector modules with defined chirality. In LEGO-LPPO-II), phosphonate-based CM of LEGO LPPO I was replaced by glycerol moiety and the synthesis was planned from enantiomerically pure starting materials using enantiospecific reactions to obtain final products with defined chirality. These new SMMTA were prepared in both configurations and testing of their antibacterial and hemolytic activities and cytotoxicities are currently under way.nThe work was supported by the project National Institute of Virology and Bacteriology (Programme EXCELES, ID Project No. LX22NPO5103) – Funded by the European Union – NextGenerationEU and Czech Health Research Council (NW24-08-00073).n

Název v anglickém jazyce

Synthesis and antibacterial activity of the second generation LEGO-LPPO

Popis výsledku anglicky

Bacterial pathogens resistant to antibiotics (ATB) are becoming an increasingly serious global problem. Current ATB targeting bacterial biosynthetic processes are facing emerging resistant strains. An attractive target for the development of antibacterial compounds is the cytoplasmic membrane as the composition of bacterial and mammalian cell membranes differs, resulting in different biophysical properties. In contrast to majority of classical antibiotics requiring metabolically active bacterial cells, membrane targeting antimicrobials are capable of also killing persistent (dormant) bacteria. Antimicrobial peptides (AMP) and host defense peptides (HDP) are examples of membrane-active compounds that represent the first line of defense in many multicellular organisms and possess a broad range of biological activities. However, their clinical usage is limited by their in vivo toxicity, stability, limited bioavailability, and large production costs. We are developing lipophosphonoxins (LPPO) – antimicrobial compounds belonging to the class of small molecule membrane targeting agents (SMMTA). Their general structure consists of four modules: a nucleoside module (NM), a polar module (PM), a hydrophobic module (HM), and a phosphonate connector module (CM). The first generation LPPO (LPPO I) demonstrated excellent bactericidal activity against various Gram-positive species. We have shown that at their bactericidal concentrations, LPPO act via the disruption of the cytoplasmic membrane. The second-generation LPPO (LPPO II) have redesigned PM to bear more polar charges. LPPO II increased their efficacy to Gram-positive and extended bactericidal activity to Gram negative bacteria. Their antibacterial activity, however, is abolished in the presence of serum albumins. By introducing LEGO-LPPO (Linker-Evolved-Group Optimized-LPPO), modular configuration was modified to include two LPPO units symmetrically attached by CM at the ends of linker module (LM), NM was omitted. Redesign of molecular skeleton brought improvements in antimicrobial activity and eliminated interactions with serum albumins. Because of chiral nature of phosphorus atoms in the connector modules the first generation LEGO-LPPO molecules are isolated as a mixture of three diastereoisomers. Here we present design and synthesis of new generation LEGO-LPPO-II based on connector modules with defined chirality. In LEGO-LPPO-II), phosphonate-based CM of LEGO LPPO I was replaced by glycerol moiety and the synthesis was planned from enantiomerically pure starting materials using enantiospecific reactions to obtain final products with defined chirality. These new SMMTA were prepared in both configurations and testing of their antibacterial and hemolytic activities and cytotoxicities are currently under way.nThe work was supported by the project National Institute of Virology and Bacteriology (Programme EXCELES, ID Project No. LX22NPO5103) – Funded by the European Union – NextGenerationEU and Czech Health Research Council (NW24-08-00073).n

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů