Colistin is a last-line antibiotic for the treatment of multidrug resistant Gram-negative bacterial infections.1 Recently, a natural ent-beyerene diterpene (ent-Beyer-15-en-18-O-oxalate) was identified as a promising inhibitor of the enzyme responsible for colistin resistance mediated by lipid A aminoarabinosylation in Gram-negative bacteria, namely, ArnT (undecaprenyl phosphate-alpha-4-amino-4-deoxy-l-arabinose arabinosyl transferase).2 To explore the structure-activity relationship (SAR), semi-synthetic analogs of hit were designed, synthesized and tested against colistin-resistant Pseudomonas aeruginosa strains, including clinical isolates (figure 1), in order to exploit the versatility of the diterpene scaffold. Microbiological assays coupled with molecular modeling demonstrated that an ent-beyerane scaffold bearing an oxalate like group at C-18/C-19, or a sugar residue at C-19 to resemble L-Ara4N is an essential requirement for a more efficient inhibition of bacterial growth likely resulting from a more efficient inhibition of ArnT activity. Importantly, the easy accessibility of ent-beyerane scaffold from Stevia rebaudiana secondary metabolites will provide a cost-effective key platform for the development of promising colistin resistance inhibitors.

DEVELOPMENT OF ArnT-MEDIATED COLISTIN RESISTANCE DITERPENE-BASED INHIBITORS / Cammarone, Silvia; Mangoni, Maria Luisa; Quaglio, Deborah; Ghirga, Francesca; Ascenzioni, Fiorentina; Botta, Bruno. - (2021). ((Intervento presentato al convegno XLV "A. Corbella" International Summer School on Organic Synthesis tenutosi a Gargnano; Italy.

DEVELOPMENT OF ArnT-MEDIATED COLISTIN RESISTANCE DITERPENE-BASED INHIBITORS

Silvia Cammarone
Primo
;
Maria Luisa Mangoni;Deborah Quaglio;Francesca Ghirga;Fiorentina Ascenzioni;Bruno Botta
2021

Abstract

Colistin is a last-line antibiotic for the treatment of multidrug resistant Gram-negative bacterial infections.1 Recently, a natural ent-beyerene diterpene (ent-Beyer-15-en-18-O-oxalate) was identified as a promising inhibitor of the enzyme responsible for colistin resistance mediated by lipid A aminoarabinosylation in Gram-negative bacteria, namely, ArnT (undecaprenyl phosphate-alpha-4-amino-4-deoxy-l-arabinose arabinosyl transferase).2 To explore the structure-activity relationship (SAR), semi-synthetic analogs of hit were designed, synthesized and tested against colistin-resistant Pseudomonas aeruginosa strains, including clinical isolates (figure 1), in order to exploit the versatility of the diterpene scaffold. Microbiological assays coupled with molecular modeling demonstrated that an ent-beyerane scaffold bearing an oxalate like group at C-18/C-19, or a sugar residue at C-19 to resemble L-Ara4N is an essential requirement for a more efficient inhibition of bacterial growth likely resulting from a more efficient inhibition of ArnT activity. Importantly, the easy accessibility of ent-beyerane scaffold from Stevia rebaudiana secondary metabolites will provide a cost-effective key platform for the development of promising colistin resistance inhibitors.
XLV "A. Corbella" International Summer School on Organic Synthesis
04 Pubblicazione in atti di convegno::04d Abstract in atti di convegno
DEVELOPMENT OF ArnT-MEDIATED COLISTIN RESISTANCE DITERPENE-BASED INHIBITORS / Cammarone, Silvia; Mangoni, Maria Luisa; Quaglio, Deborah; Ghirga, Francesca; Ascenzioni, Fiorentina; Botta, Bruno. - (2021). ((Intervento presentato al convegno XLV "A. Corbella" International Summer School on Organic Synthesis tenutosi a Gargnano; Italy.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1558529
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