A Long Residence Time Enoyl-Reductase Inhibitor Explores an Extended Binding Region with Isoenzyme-Dependent Tautomer Adaptation and Differential Substrate-Binding Loop Closure

• DOI: 10.1021/acsinfecdis.0c00437
• Publication Date: 2021-03-12T19:33:45Z
• Authors: Sandra Eltschkner; Josef Kehrein; Thien Anh Le; Shabnam Davoodi; Benjamin Merget; Sneha Basak; Jonas D. Weinrich; Johannes Schiebel; Peter J. Tonge; Bernd Engels; Christoph Sotriffer; Caroline Kisker
• Keywords: Isoenzymes; 0301 basic medicine; Staphylococcus aureus; 03 medical and health sciences; Isomerism; Mycobacterium tuberculosis; Enzyme Inhibitors; Oxidoreductases; 3. Good health

The enoyl-acyl carrier protein (ACP) reductase (ENR) is a key enzyme within the bacterial fatty-acid synthesis pathway. It has been demonstrated that small-molecule inhibitors carrying diphenylether (DPE) scaffold bear great potential for development of highly specific and effective drugs against this class. Interestingly, different substitution patterns DPE have shown to lead varying effects on kinetic thermodynamic behavior toward ENRs from organisms. Here, we investigated effect 4'-pyridone substituent in context slow tight-binding inhibitor SKTS1 inhibition Staphylococcus aureus enoyl-ACP-reductase saFabI closely related isoenzyme Mycobacterium tuberculosis, InhA, explored new interaction site substrate-binding pocket. Using high-resolution crystal structures both complexes combination with molecular dynamics (MD) simulations, measurements, quantum mechanical (QM) calculations, provide evidence adopts tautomeric forms when bound two ENRs. We furthermore elucidate structural determinants leading significant differences residence time enzymes.