jm6b00580_si_003.pdb (1.54 kB)
Download file

The Rational Design, Synthesis, and Antimicrobial Properties of Thiophene Derivatives That Inhibit Bacterial Histidine Kinases

Download (1.54 kB)
posted on 30.08.2016, 00:00 by Thibaut Boibessot, Christopher P. Zschiedrich, Alexandre Lebeau, David Bénimèlis, Catherine Dunyach-Rémy, Jean-Philippe Lavigne, Hendrik Szurmant, Zohra Benfodda, Patrick Meffre
The 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.