AtoSC two-component system participates in many indispensable processes of Escherichia coli. We report here that the AtoSC signal transduction is inhibited by established histidine kinase inhibitors. Closantel, RWJ-49815 and TNP-ATP belonging to different chemical classes of inhibitors, abrogated the in vitro AtoS kinase autophosphorylation. However, when AtoS was embedded in the membrane fractions, higher inhibitor concentrations were required for total inhibition. When AtoS interacted with AtoC forming complex, the intrinsic histidine kinase was protected by the response regulator, requiring increased inhibitors concentrations for partially AtoS autophosphorylation reduction. The inhibitors exerted an additional function on AtoSC, blocking the phosphotransfer from AtoS to AtoC, without however, affecting AtoC~P dephosphorylation. Their in vivo consequences through the AtoSC inhibition were elucidated on atoDAEB operon expression, which was inhibited only in AtoSC-expressing bacteria where AtoSC was induced by acetoacetate or spermidine. The inhibitor effects were extended on the AtoSC regulatory role on cPHB [complexed poly-(R)-3-hydroxybutyrate] biosynthesis. cPHB was decreased upon the blockers only in acetoacetate-induced AtoSC-expressing cells. Increased ATP amounts during bacterial growth reversed the inhibitory TNP-ATP-mediated effect on cPHB. The alteration of pivotal E. coli processes as an outcome of AtoSC inhibition, establish this system as a target of two-component systems inhibitors.

01 Jul 1999·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Antifungal Properties and Target Evaluation of Three Putative Bacterial Histidine Kinase Inhibitors

Q2 · MEDICINE

Article

Author: Lin, Hong ; Deschenes, Robert J. ; Fassler, Jan S. ; Ault, Addison D.

ABSTRACT Histidine protein kinases have been explored as potential antibacterial drug targets. The recent identification of two-component histidine kinases in fungi has led us to investigate the antifungal properties of three bacterial histidine kinase inhibitors (RWJ-49815, RWJ-49968, and RWJ-61907). All three compounds were found to inhibit growth of the Saccharomyces cerevisiae and Candida albicans strains, with MICs ranging from 1 to 20 μg/ml. However, deletion of SLN1 , the only histidine kinase in S. cerevisiae , did not alter drug efficacy. In vitro kinase assays were performed by using the Sln1 histidine kinase purified from bacteria as a fusion protein to glutathione S -transferase. RWJ-49815 and RWJ-49968 inhibited kinase a 50% inhibitory concentration of 10 μM, whereas RWJ-61907 failed to inhibit at concentrations up to 100 μM. Based on these results, we conclude that these compounds have antifungal properties; however, their mode of action appears to be independent of histidine kinase inhibition.

28 Apr 1998·Proceedings of the National Academy of SciencesQ1 · CROSS-FIELD

Antibacterial agents that inhibit two-component signal transduction systems

Q1 · CROSS-FIELD

Article

Author: Bernstein, J. ; Whiteley, J. M. ; Frosco, M. B. ; Hlasta, D. J. ; Ohemeng, K. ; Klaubert, D. H. ; Demers, J. P. ; Hoch, J. A. ; Huang, S. ; Lawrence, L. E. ; Barrett, J. F. ; Goldschmidt, R. M. ; Foleno, B. ; Johnson, S. ; Donetz, A. ; Chen, R. ; Licata, L. ; Macielag, M. J. ; Kanojia, R. ; Frechette, R. ; Fernandez, J. ; Wang, L.

A class of antibacterials has been discovered that inhibits the growth of Gram-positive pathogenic bacteria. RWJ-49815, a representative of a family of hydrophobic tyramines, in addition to being a potent bactericidal Gram-positive antibacterial, inhibits the autophosphorylation of kinase A of the KinA∷Spo0F two-component signal transduction system in vitro . Analogs of RWJ-49815 vary greatly in their ability to inhibit growth of bacteria and this ability correlates directly with their activity as kinase A inhibitors. Compared with the potent quinolone, ciprofloxacin, RWJ-49815 exhibits reduced resistance emergence in a laboratory passage experiment. Inhibition of the histidine protein kinase∷response regulator two-component signal transduction pathways may present an opportunity to depress chromosomal resistance emergence by targeting multiple proteins with a single inhibitor in a single bacterium. Such inhibitors may represent a class of antibacterials that potentially may represent a breakthrough in antibacterial therapy.

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Indication	Highest Phase	Country/Location	Organization	Date
Bacterial Infections	Preclinical	US	Johnson & Johnson Pharmaceutical Research & Development LLC	-

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