Revisiting the β-Lactams for Tuberculosis Therapy with a Compound-Compound Synthetic Lethality Approach.

Area of Science:

• Microbiology
• Medicinal Chemistry
• Drug Discovery

Background:

• Beta-lactam antibiotics show limited effectiveness against Mycobacterium tuberculosis.
• Existing treatments for drug-resistant tuberculosis are scarce, necessitating novel therapeutic strategies.
• A case study showed promise using meropenem combined with a beta-lactamase inhibitor for extensively drug-resistant tuberculosis.

Purpose of the Study:

• To identify small molecules that can sensitize Mycobacterium tuberculosis to meropenem.
• To investigate novel targets involved in innate beta-lactam resistance in Mycobacterium tuberculosis.
• To develop new therapeutic approaches for combating drug-resistant tuberculosis.

Main Methods:

• Screening of a small-molecule library to find compounds potentiating meropenem activity.
• Verification of synthetic lethality phenotype for identified hit compounds.
• Oral bioavailability studies in mice and structure-activity relationship analyses.
• Transcriptional profiling to elucidate the mechanism of action and identify potential targets.

Main Results:

• Six hit compounds were identified, belonging to N-arylindole and benzothiophene chemotypes.
• Three N-arylindole derivatives and one benzothiophene derivative demonstrated a synthetic lethality phenotype.
• One benzothiophene derivative showed partial oral bioavailability in mice.
• Analogs with potent antitubercular activity were identified, effective alone or with meropenem.

Conclusions:

• Novel small molecules potentiate meropenem activity against Mycobacterium tuberculosis, likely by inhibiting innate resistance mechanisms.
• Beta-lactam compound-compound synthetic lethality screening presents a promising strategy for developing new treatments for drug-resistant tuberculosis.
• Further research into these compounds and their targets could lead to effective therapies for tuberculosis.