Thibaut Boibessot1, Christopher P Zschiedrich2,3, Alexandre Lebeau1, David Bénimèlis1, Catherine Dunyach-Rémy4, Jean-Philippe Lavigne4, Hendrik Szurmant2,3, Zohra Benfodda1,5, Patrick Meffre1,5. 1. EA7352 CHROME, Rue du Dr G. Salan, University of Nîmes , 30021 Nîmes cedex 1, France. 2. Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences , Pomona, California 91766, United States. 3. Department of Molecular and Experimental Medicine, The Scripps Research Institute , La Jolla, California 92037, United States. 4. Institut National de la Santé et de la Recherche Médicale, U1047, Montpellier University , CHU de Nîmes, Place du Pr R. Debré, 30029 Nîmes, France. 5. IBMM, UMR-CNRS5247, Université de Montpellier , Place Eugène Bataillon, 34095 Montpellier, France.
Abstract
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.
The emergence of multidrug-resistant bacteria emphasizes the urgent need for novel antin class="Chemical">bacterial 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 <spn>an class="Chemical">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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