Colistin is a last-resort antibiotic for the treatment of multidrug resistant Gram-negative bacterial infections. Recently, a natural ent-beyerene diterpene 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). Here, semisynthetic analogues of hit were designed, synthetized, and tested against colistin-resistant Pseudomonas aeruginosa strains including clinical isolates to exploit the versatility of the diterpene scaffold. Microbiological assays coupled with molecular modeling indicated that for a more efficient colistin adjuvant activity, likely resulting from inhibition of the ArnT activity by the selected compounds and therefore from their interaction with the catalytic site of ArnT, an ent-beyerane scaffold is required along with an oxalate-like group at C-18/C-19 or a sugar residue at C-19 to resemble L-Ara4N. The ent-beyerane skeleton is identified for the first time as a privileged scaffold for further cost-effective development of valuable colistin resistance inhibitors.

Ent-beyerane diterpenes as a key platform for the development of arnt-mediated colistin resistance inhibitors / Quaglio, D.; Mangoni, M. L.; Stefanelli, R.; Corradi, S.; Casciaro, B.; Vergine, V.; Lucantoni, F.; Cavinato, L.; Cammarone, S.; Loffredo, M. R.; Cappiello, F.; Calcaterra, A.; Erazo, S.; Ghirga, F.; Mori, M.; Imperi, F.; Ascenzioni, F.; Botta, B.. - In: JOURNAL OF ORGANIC CHEMISTRY. - ISSN 0022-3263. - 85:16(2020), pp. 10891-10901. [10.1021/acs.joc.0c01459]

Ent-beyerane diterpenes as a key platform for the development of arnt-mediated colistin resistance inhibitors

Quaglio D.;Mangoni M. L.;Stefanelli R.;Corradi S.;Casciaro B.;Vergine V.;Lucantoni F.;Cavinato L.;Cammarone S.;Loffredo M. R.;Cappiello F.;Calcaterra A.;Ghirga F.
;
Imperi F.;Ascenzioni F.;Botta B.
2020

Abstract

Colistin is a last-resort antibiotic for the treatment of multidrug resistant Gram-negative bacterial infections. Recently, a natural ent-beyerene diterpene 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). Here, semisynthetic analogues of hit were designed, synthetized, and tested against colistin-resistant Pseudomonas aeruginosa strains including clinical isolates to exploit the versatility of the diterpene scaffold. Microbiological assays coupled with molecular modeling indicated that for a more efficient colistin adjuvant activity, likely resulting from inhibition of the ArnT activity by the selected compounds and therefore from their interaction with the catalytic site of ArnT, an ent-beyerane scaffold is required along with an oxalate-like group at C-18/C-19 or a sugar residue at C-19 to resemble L-Ara4N. The ent-beyerane skeleton is identified for the first time as a privileged scaffold for further cost-effective development of valuable colistin resistance inhibitors.
natural product chemistry; colistin resistance; diterpenes
01 Pubblicazione su rivista::01a Articolo in rivista
Ent-beyerane diterpenes as a key platform for the development of arnt-mediated colistin resistance inhibitors / Quaglio, D.; Mangoni, M. L.; Stefanelli, R.; Corradi, S.; Casciaro, B.; Vergine, V.; Lucantoni, F.; Cavinato, L.; Cammarone, S.; Loffredo, M. R.; Cappiello, F.; Calcaterra, A.; Erazo, S.; Ghirga, F.; Mori, M.; Imperi, F.; Ascenzioni, F.; Botta, B.. - In: JOURNAL OF ORGANIC CHEMISTRY. - ISSN 0022-3263. - 85:16(2020), pp. 10891-10901. [10.1021/acs.joc.0c01459]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1444335
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