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Download fileThe Rational Design, Synthesis, and Antimicrobial Properties of Thiophene Derivatives That Inhibit Bacterial Histidine Kinases
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posted on 2016-08-30, 00:00 authored by Thibaut Boibessot, Christopher
P. Zschiedrich, Alexandre Lebeau, David Bénimèlis, Catherine Dunyach-Rémy, Jean-Philippe Lavigne, Hendrik Szurmant, Zohra Benfodda, Patrick MeffreThe emergence of
multidrug-resistant bacteria emphasizes the urgent
need for novel antibacterial compounds targeting unique cellular processes.
Two-component signal transduction systems (TCSs) are commonly used
by bacteria to couple environmental stimuli to adaptive responses,
are absent in mammals, and are embedded in various pathogenic pathways.
To attenuate these signaling pathways, we aimed to target the TCS
signal transducer histidine kinase (HK) by focusing on their highly
conserved adenosine triphosphate-binding domain. We used a structure-based
drug design strategy that begins from an inhibitor-bound crystal structure
and includes a significant number of structurally simplifiying “intuitive”
modifications to arrive at the simple achiral, biaryl target structures.
Thus, ligands were designed, leading to a series of thiophene derivatives.
These compounds were synthesized and evaluated in vitro against bacterial
HKs. We identified eight compounds with significant inhibitory activities
against these proteins, two of which exhibited broad-spectrum antimicrobial
activity. The compounds were also evaluated as adjuvants for the treatment
of resistant bacteria. One compound was found to restore the sensivity
of these bacteria to the respective antibiotics.
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Keywords
biaryl target structuresinhibitor-bound crystal structuremultidrug-resistant bacteriaTCS signal transducer histidine kinasebroad-spectrum antimicrobial activityadaptive responsesRational DesignTwo-component signal transduction systemsadenosine triphosphate-binding domaincompoundHKAntimicrobial PropertiesHistidine Kinasespathwaythiophene derivativesThiophene Derivativesstructure-based drug design strategy