Putative histidine kinase inhibitors with antibacterial effect against multi-drug resistant clinical isolates identified by in vitro and in silico screens

Nadya Velikova, Simone Fulle, Ana Sousa Manso, Milena Mechkarska, Paul Finn, J. Michael Conlon, Marco Rinaldo Oggioni, Jerry M. Wells, Alberto Marina

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37 Citations (Scopus)


Novel antibacterials are urgently needed to address the growing problem of bacterial resistance to conventional antibiotics. Two-component systems (TCS) are widely used by bacteria to regulate gene expression in response to various environmental stimuli and physiological stress and have been previously proposed as promising antibacterial targets. TCS consist of a sensor histidine kinase (HK) and an effector response regulator. The HK component contains a highly conserved ATP-binding site that is considered to be a promising target for broad-spectrum antibacterial drugs. Here, we describe the identification of putative HK autophosphorylation inhibitors following two independent experimental approaches: in vitro fragment-based screen via differential scanning fluorimetry and in silico structure-based screening, each followed up by the exploration of analogue compounds as identified by ligand-based similarity searches. Nine of the tested compounds showed antibacterial effect against multi-drug resistant clinical isolates of bacterial pathogens and include three novel scaffolds, which have not been explored so far in other antibacterial compounds. Overall, putative HK autophosphorylation inhibitors were found that together provide a promising starting point for further optimization as antibacterials.

Original languageEnglish
Article number26085
JournalScientific Reports
Publication statusPublished (in print/issue) - 13 May 2016

Bibliographical note

Funding Information:
We thank all colleagues from the STARS ITN (EU FP7 Marie Curie ITN grant no. 238490) for their valuable comments during meetings. We thank Jean Paul Ebejer PhD for help in choosing the fragment-library, Tibor Pal PhD and Agnes Sonnevend PhD, Department of Medical Microbiology, UAE University for supply of bacterial strains, and Manju Prajeep, Biochemistry Department, UAE University, for technical help. This work was supported by the European Union Framework Programme 7-funded Marie Curie Initial Training Nework STARS (Contract No. PITN-GA-2009-238490, J.M.W., M.R.O, P.F., A.M.), H2020 MSCA IF (AND-659121, N.V.), and by grant BIO2013-42619-P from the Ministerio de Economia y Competitividad (A.M.). N.V., A.S. and S.F. were recipients of Marie Curie Fellowships.

Publisher Copyright:
© 2016, Nature Publishing Group. All rights reserved.


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