Quaglio Deborah, Mangoni Maria Luisa, Stefanelli Roberta, Corradi Silvia, Casciaro Bruno, Vergine Valeria, Lucantoni Federica, Cavinato Luca, Cammarone Silvia, Loffredo Maria Rosa, Cappiello Floriana, Calcaterra Andrea, Erazo Silvia, Ghirga Francesca, Mori Mattia, Imperi Francesco, Ascenzioni Fiorentina, Botta Bruno
Department of Chemistry and Technology of Drugs, "Department of Excellence 2018-2022", Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy.
Laboratory Affiliated to Pasteur Italia-Fondazione Cenci Bolognetti, Department of Biochemical Sciences, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy.
J Org Chem. 2020 Aug 21;85(16):10891-10901. doi: 10.1021/acs.joc.0c01459. Epub 2020 Aug 10.
Colistin is a last-resort antibiotic for the treatment of multidrug resistant Gram-negative bacterial infections. Recently, a natural -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 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 -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 -beyerane skeleton is identified for the first time as a privileged scaffold for further cost-effective development of valuable colistin resistance inhibitors.
黏菌素是治疗多重耐药革兰氏阴性菌感染的最后一道抗生素防线。最近，一种天然的贝壳杉烯二萜被鉴定为一种有前景的酶抑制剂，该酶负责革兰氏阴性菌中由脂多糖氨基阿拉伯糖基化介导的黏菌素耐药性，即ArnT（十一异戊二烯磷酸-α-4-氨基-4-脱氧-L-阿拉伯糖阿拉伯糖基转移酶）。在此，设计、合成了该命中化合物的半合成类似物，并针对包括临床分离株在内的耐黏菌素菌株进行了测试，以利用二萜支架的多功能性。微生物学测定与分子建模表明，为了获得更有效的黏菌素佐剂活性，这可能是由于所选化合物抑制了ArnT活性，进而与ArnT的催化位点相互作用导致的，需要一个贝壳杉烷支架以及在C-18/C-19处的类似草酸盐基团或在C-19处的糖残基以类似L-Ara4N。贝壳杉烷骨架首次被确定为一种有优势的支架，可用于进一步经济高效地开发有价值的黏菌素耐药性抑制剂。
