A novel colistin adjuvant identified by virtual screening for ArnT inhibitors

Abstract Background Colistin is a last-resort treatment option for many MDR Gram-negative bacteria. The covalent addition of l-aminoarabinose to the lipid A moiety of LPS is the main colistin resistance mechanism in the human pathogen Pseudomonas aeruginosa. Objectives Identification (by in silico s...

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Veröffentlicht in:Journal of antimicrobial chemotherapy 2020-09, Vol.75 (9), p.2564-2572
Hauptverfasser: Ghirga, Francesca, Stefanelli, Roberta, Cavinato, Luca, Lo Sciuto, Alessandra, Corradi, Silvia, Quaglio, Deborah, Calcaterra, Andrea, Casciaro, Bruno, Loffredo, Maria Rosa, Cappiello, Floriana, Morelli, Patrizia, Antonelli, Alberto, Rossolini, Gian Maria, Mangoni, Marialuisa, Mancone, Carmine, Botta, Bruno, Mori, Mattia, Ascenzioni, Fiorentina, Imperi, Francesco
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Sprache:eng
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Zusammenfassung:Abstract Background Colistin is a last-resort treatment option for many MDR Gram-negative bacteria. The covalent addition of l-aminoarabinose to the lipid A moiety of LPS is the main colistin resistance mechanism in the human pathogen Pseudomonas aeruginosa. Objectives Identification (by in silico screening of a chemical library) of potential inhibitors of ArnT, which catalyses the last committed step of lipid A aminoarabinosylation, and their validation in vitro as colistin adjuvants. Methods The available ArnT crystal structure was used for a docking-based virtual screening of an in-house library of natural products. The resulting putative ArnT inhibitors were tested in growth inhibition assays using a reference colistin-resistant P. aeruginosa strain. The most promising compound was further characterized for its range of activity, specificity and cytotoxicity. Additionally, the effect of the compound on lipid A aminoarabinosylation was verified by MS analyses of lipid A. Results A putative ArnT inhibitor (BBN149) was discovered by molecular docking and demonstrated to specifically potentiate colistin activity in colistin-resistant P. aeruginosa isolates, without relevant effect on colistin-susceptible strains. BBN149 also showed adjuvant activity against colistin-resistant Klebsiella pneumoniae and low toxicity to bronchial epithelial cells. Lipid A aminoarabinosylation was reduced in BBN149-treated cells, although only partially. Conclusions This study demonstrates that in silico screening targeting ArnT can successfully identify inhibitors of colistin resistance and provides a promising lead compound for the development of colistin adjuvants for the treatment of MDR bacterial infections.
ISSN:0305-7453
1460-2091
DOI:10.1093/jac/dkaa200