Thioquinazolinones as Antituberculosis Agents Targeting Phosphopantetheinyl Transferase

Area of Science:

• Medicinal Chemistry
• Microbiology
• Drug Discovery

Background:

• The enzyme phosphopantetheinyl transferase (PptT) is crucial for Mycobacterium tuberculosis (Mtb) survival and represents a potential drug target.
• Existing antituberculosis treatments face challenges with drug resistance and toxicity.

Purpose of the Study:

• To identify novel inhibitors of Mtb PptT.
• To investigate the structure-activity relationship (SAR) of identified hit compounds.
• To evaluate the efficacy and mechanism of action of these compounds against Mtb.

Main Methods:

• High-throughput screening of chemical libraries to identify PptT inhibitors.
• Structure-activity relationship (SAR) studies to optimize lead compounds.
• In vitro and in cellulo assays using Mtb strains (including hypomorphic and mutant strains) and macrophages.
• Off-target and toxicity assessments (cytotoxicity, receptor binding, glutathione reactivity).

Main Results:

• Identification of (pyridin-3-ylmethyl)-substituted thioquinazolinones as PptT inhibitors.
• Thioquinazolinones demonstrated on-target, whole-cell activity against Mtb in axenic culture and macrophages, comparable to current drugs.
• Compound efficacy was confirmed by increased susceptibility in a PptT hypomorphic strain and resistance in PptT mutant strains.
• Compounds showed selectivity, with no significant activity against other bacteria, low mammalian cytotoxicity, and minimal off-target binding.

Conclusions:

• Thioquinazolinones are effective on-target inhibitors of Mtb PptT.
• These compounds exhibit promising efficacy and safety profiles for potential antituberculosis drug development.
• Further investigation into the metabolic fate (methylation) of these compounds in Mtb is warranted.