ABSTRACT
Tuberculosis is the leading cause of death worldwide from infectious diseases. With the development of drug-resistant strains of Mycobacterium tuberculosis, there is an acute need for new medicines with novel modes of action. Herein, we report the discovery and profiling of a novel hydantoin-based family of antimycobacterial inhibitors of the decaprenylphospho-ß-d-ribofuranose 2-oxidase (DprE1). In this study, we have prepared a library of more than a 100 compounds and evaluated them for their biological and physicochemical properties. The series is characterized by high enzymatic and whole-cell activity, low cytotoxicity, and a good overall physicochemical profile. In addition, we show that the series acts via reversible inhibition of the DprE1 enzyme. Overall, the novel compound family forms an attractive base for progression to further stages of optimization and may provide a promising drug candidate in the future.
Subject(s)
Alcohol Oxidoreductases/antagonists & inhibitors , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Hydantoins/chemistry , Actinobacteria/drug effects , Alcohol Oxidoreductases/metabolism , Bacterial Proteins/metabolism , Drug Stability , Enzyme Inhibitors/chemistry , Hep G2 Cells , High-Throughput Screening Assays/methods , Humans , Macrophages/microbiology , Microbial Sensitivity Tests , Mycobacterium tuberculosis/drug effects , Reproducibility of Results , Structure-Activity Relationship , Tuberculosis/drug therapy , Tuberculosis/microbiologyABSTRACT
Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment.
Subject(s)
Antitubercular Agents/pharmacology , Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/enzymology , Animals , Antitubercular Agents/chemistry , Binding Sites , Catalytic Domain , Disease Models, Animal , Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/genetics , Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/metabolism , Enzyme Inhibitors/chemistry , Female , Humans , Mice , Microbial Sensitivity Tests , Microsomes , Models, Molecular , Mutation , Mycobacterium tuberculosis/genetics , Protein Binding , Protein Conformation , Tuberculosis/drug therapy , Tuberculosis/microbiology , Tuberculosis/mortality , Tuberculosis, Multidrug-ResistantABSTRACT
The concept of antimicrobial susceptibility testing is an essential part of clinical microbiology. Antimicrobial testing has played a central role in the identification of new antibiotics and defining their clinical uses. Here we describe different approaches to determine the activity of compounds in medium- or high-throughput format.
