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Updated: Jun 10, 2026

Assay Development for High-Throughput Drug Screening Against Mycobacteria
Published on: October 25, 2024
Synthesis of 4-Aminoindole-Containing Cephalosporin Prodrugs and Their Biological Activity against Mycobacterium
Sangmi Oh1, Helena I M Boshoff1, Jose Santinni O Roma1
1Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland 20892, United States.
Abstract:
Indole 4-carboxamides are promising prodrugs that liberate 4-aminoindole, which poisons tryptophan biosynthesis in Mycobacterium tuberculosis (Mtb). Limiting enthusiasm for these compounds is the high rate of emergence of resistance since the amidase, which liberates the 4-aminoindole core, is nonessential. To overcome this limitation, we designed bifunctional β-lactams that, upon hydrolytic opening of the β-lactam ring, liberate 4-aminoindole. These bifunctional molecules had good potency against Mtb, which could be rescued by exogenous l-tryptophan addition. In contrast to the parental indole 4-carboxamides, resistant mutants to these bifunctional compounds developed at a much lower frequency than the parental compounds in vitro, supporting this strategy as a means to protect these agents from rapid development of resistance.
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