1. anti-HIV Natural Product (+)-Calanolide A Is Active Against Both Drug-Susceptible and Drug-Resistant Strains of Mycobacterium tuberculosis
- Author
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Ze-Qi Xu, William J. Suling, Esther W. Barrow, William W. Barrow, Yuh-Meei Lin, Louise Westbrook, and Michael T. Flavin
- Subjects
Tuberculosis ,Anti-HIV Agents ,medicine.drug_class ,Mitomycin ,Clinical Biochemistry ,Antibiotics ,Antitubercular Agents ,Pharmaceutical Science ,Microbial Sensitivity Tests ,Calanolide A ,Drug resistance ,Virus Replication ,Antimycobacterial ,Pyranocoumarins ,Biochemistry ,Cell Line ,Microbiology ,Mycobacterium tuberculosis ,Inhibitory Concentration 50 ,Coumarins ,Antineoplastic Combined Chemotherapy Protocols ,Chlorocebus aethiops ,Drug Resistance, Bacterial ,Drug Discovery ,medicine ,Animals ,Ifosfamide ,Vero Cells ,Molecular Biology ,Antibacterial agent ,biology ,DNA synthesis ,Chemistry ,Macrophages ,Organic Chemistry ,RNA ,Biological activity ,DNA ,General Medicine ,biology.organism_classification ,medicine.disease ,Mechanism of action ,Molecular Medicine ,Cisplatin ,Rifampin ,medicine.symptom - Abstract
Naturally occurring anti-HIV-1 agent (+)-calanolide A was found to be active against all of the strains of Mycobacterium tuberculosis tested, including those resistant to the standard antitubercular drugs. Efficacy evaluations in macrophages revealed that (+)-calanolide A significantly inhibited intracellular replication of M. tuberculosis H37Rv at concentrations below the MIC observed in vitro. Preliminary mechanistic studies indicated that (+)-calanolide A rapidly inhibits RNA and DNA synthesis followed by an inhibition of protein synthesis. Compared with known inhibitors, this scenario is more similar to effects observed with rifampin, an inhibitor of RNA synthesis. Since (+)-calanolide A was active against a rifampin-resistant strain, it is believed that these two agents may involve different targets. (+)-Calanolide A and its related pyranocoumarins are the first class of compounds identified to possess antimycobacterial and antiretroviral activities, representing a new pharmacophore for anti-TB activity.
- Published
- 2004