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PaFabF_VS_chemrxiv_plus_sup_mat.pdf (4.4 MB)

An Experimental Toolbox for Structure-Based Hit Discovery for P. Aeruginosa FabF, a Promising Target for Antibiotics

submitted on 30.04.2021, 14:39 and posted on 03.05.2021, 08:15 by Ludvik Olai Espeland, Charis Georgiou, Raphael Klein, Hemalatha Bhukya, Bengt Erik Haug, Jarl Underhaug, Prathama S. Mainkar, Ruth Brenk
FabF (3-oxoacyl-[acyl-carrier-protein] synthase 2), which catalyses the rate limiting condensation reaction in the fatty acid synthesis II pathway, is an attractive target for new antibiotics. Here, we focus on FabF from P. aeruginosa (PaFabF) as antibiotics against this pathogen are urgently needed. To facilitate exploration of this target we have set up an experimental toolbox consisting of binding assays using bio-layer interferometry as well as saturation transfer difference (STD) and WaterLOGSY NMR in addition to robust conditions for structure determination. The suitability of the toolbox to support structure-based design of FabF inhibitors was demonstrated through the validation of hits obtained from virtual screening. Screening of our in-house library of almost 5 million compounds resulted in 6 compounds for which binding into the malonyl-binding site of FabF was shown. For one of the hits, the crystal structure in complex with PaFabF was determined. Based on the obtained binding mode, analogues were designed and synthesised, but affinity could not be improved. This work has laid the foundation for structure-based exploration of PaFabF.


Structure-based exploration for the detection of new starting structures for antibiotics

The Research Council of Norway

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AMR/IN/111/2017‐ECD‐II (Indian Council of Medical Research)

Melzer Research Fund

National consortium of Crystallography

The Research Council of Norway

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245922, Research council of Norway

Bergen Research Foundation

Sparebankstiftinga Sogn og Fjordane

NNP - The Norwegian NMR Platform

The Research Council of Norway

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Email Address of Submitting Author


University of Bergen, Department of Biomedicine



ORCID For Submitting Author


Declaration of Conflict of Interest

No conflict of interests.