title: Putative histidine kinase inhibitors with antibacterial effect against multi-drug resistant clinical isolates identified by in vitro and in silico screens.
abstract: 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.
authors.affiliation: Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas (CSIC), Jaume Roig 11, 46010 Valencia, Spain.|Host-Microbe Interactomics Chair Group, Animal Sciences, University of Wageningen, P.O. Box 338, 6700 AH Wageningen, The Netherlands.
authors.forename: Nadya
authors.initials: N
authors.lastname: Velikova
authors.affiliation: InhibOx Limited, Oxford, OX1 1BY, United Kingdom.
authors.forename: Simone
authors.initials: S
authors.lastname: Fulle
authors.affiliation: Dipartimento di Biotecnologie Mediche, Universita di Siena, 53100 Siena, Italy.|Department of Genetics, University of Leicester, Leicester, Le1 7RH, United Kingdom.
authors.forename: Ana Sousa
authors.initials: AS
authors.lastname: Manso
authors.affiliation: Department of Biochemistry, College of Medicine and Health Science, United Arab Emirates Univesity, P.O. Box 17666 Al Ain, United Arab Emirates.
authors.forename: Milena
authors.initials: M
authors.lastname: Mechkarska
authors.affiliation: InhibOx Limited, Oxford, OX1 1BY, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Finn
authors.affiliation: Department of Biochemistry, College of Medicine and Health Science, United Arab Emirates Univesity, P.O. Box 17666 Al Ain, United Arab Emirates.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Conlon
authors.affiliation: Dipartimento di Biotecnologie Mediche, Universita di Siena, 53100 Siena, Italy.|Department of Genetics, University of Leicester, Leicester, Le1 7RH, United Kingdom.
authors.forename: Marco Rinaldo
authors.initials: MR
authors.lastname: Oggioni
authors.affiliation: Host-Microbe Interactomics Chair Group, Animal Sciences, University of Wageningen, P.O. Box 338, 6700 AH Wageningen, The Netherlands.
authors.forename: Jerry M
authors.initials: JM
authors.lastname: Wells
authors.affiliation: Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas (CSIC), Jaume Roig 11, 46010 Valencia, Spain.|CIBER de Enfermedades Raras (CIBERER), ISCIII, Valencia, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Marina
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001424:Bacterial Infections / Q000188:drug therapy*; D001669:Biochemical Phenomena; D055808:Drug Discovery; D018432:Drug Resistance, Multiple; D015964:Gene Expression Regulation, Bacterial; D000071677:Histidine Kinase / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D047428:Protein Kinase Inhibitors; D000071677:Histidine Kinase