Skip to Content
Merck
  • Verapamil, and its metabolite norverapamil, inhibit macrophage-induced, bacterial efflux pump-mediated tolerance to multiple anti-tubercular drugs.

Verapamil, and its metabolite norverapamil, inhibit macrophage-induced, bacterial efflux pump-mediated tolerance to multiple anti-tubercular drugs.

The Journal of infectious diseases (2014-02-18)
Kristin N Adams, John D Szumowski, Lalita Ramakrishnan
ABSTRACT

Drug tolerance likely represents an important barrier to tuberculosis treatment shortening. We previously implicated the Mycobacterium tuberculosis efflux pump Rv1258c as mediating macrophage-induced tolerance to rifampicin and intracellular growth. In this study, we infected the human macrophage-like cell line THP-1 with drug-sensitive and drug-resistant M. tuberculosis strains and found that tolerance developed to most antituberculosis drugs, including the newer agents moxifloxacin, PA-824, linezolid, and bedaquiline. Multiple efflux pump inhibitors in clinical use for other indications reversed tolerance to isoniazid and rifampicin and slowed intracellular growth. Moreover, verapamil reduced tolerance to bedaquiline and moxifloxacin. Verapamil's R isomer and its metabolite norverapamil have substantially less calcium channel blocking activity yet were similarly active as verapamil at inhibiting macrophage-induced drug tolerance. Our finding that verapamil inhibits intracellular M. tuberculosis growth and tolerance suggests its potential for treatment shortening. Norverapamil, R-verapamil, and potentially other derivatives present attractive alternatives that may have improved tolerability.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Rifampicin, suitable for plant cell culture, BioReagent, ≥95% (HPLC), powder or crystals
Sign Into View Organizational & Contract Pricing
Sigma-Aldrich
(±)-Norverapamil hydrochloride, ≥98% (HPLC)
Sign Into View Organizational & Contract Pricing
Sigma-Aldrich
Rifampicin, ≥95% (HPLC), powder or crystals
Sign Into View Organizational & Contract Pricing
Sigma-Aldrich
Ethionamide
Sign Into View Organizational & Contract Pricing
Sigma-Aldrich
(±)-Verapamil hydrochloride, ≥99% (titration), powder
Sign Into View Organizational & Contract Pricing
Sigma-Aldrich
Rifabutin, >98% (HPLC), powder
Sign Into View Organizational & Contract Pricing
Supelco
(±)-Verapamil hydrochloride, Pharmaceutical Secondary Standard; Certified Reference Material
Sign Into View Organizational & Contract Pricing
USP
Rifabutin, United States Pharmacopeia (USP) Reference Standard
Sign Into View Organizational & Contract Pricing
Supelco
Verapamil hydrochloride solution, 1.0 mg/mL in methanol (as free base), ampule of 1 mL, certified reference material, Cerilliant®
Sign Into View Organizational & Contract Pricing
Rifabutin, European Pharmacopoeia (EP) Reference Standard
Sign Into View Organizational & Contract Pricing
Ethionamide, European Pharmacopoeia (EP) Reference Standard
Sign Into View Organizational & Contract Pricing
Sigma-Aldrich
Piperine, ≥95%, FG
Sign Into View Organizational & Contract Pricing
Sigma-Aldrich
D-Cycloserine
Sign Into View Organizational & Contract Pricing
Sigma-Aldrich
D-Cycloserine
Sign Into View Organizational & Contract Pricing
Supelco
Isoniazid, analytical standard, ≥99% (TLC)
Sign Into View Organizational & Contract Pricing
Sigma-Aldrich
Clofazimine
Sign Into View Organizational & Contract Pricing
Sigma-Aldrich
D-Cycloserine, synthetic
Sign Into View Organizational & Contract Pricing
USP
Verapamil hydrochloride, United States Pharmacopeia (USP) Reference Standard
Sign Into View Organizational & Contract Pricing
Supelco
Piperine, analytical standard
Sign Into View Organizational & Contract Pricing
Rifampicin, European Pharmacopoeia (EP) Reference Standard
Sign Into View Organizational & Contract Pricing
Ethionamide for system suitability, European Pharmacopoeia (EP) Reference Standard
Sign Into View Organizational & Contract Pricing
Isoniazid, European Pharmacopoeia (EP) Reference Standard
Sign Into View Organizational & Contract Pricing
Piperine, European Pharmacopoeia (EP) Reference Standard
Sign Into View Organizational & Contract Pricing
Clofazimine, European Pharmacopoeia (EP) Reference Standard
Sign Into View Organizational & Contract Pricing
Verapamil hydrochloride, European Pharmacopoeia (EP) Reference Standard
Sign Into View Organizational & Contract Pricing
Sigma-Aldrich
Piperine, ≥97%
Sign Into View Organizational & Contract Pricing
Sigma-Aldrich
4-Aminosalicylic acid, 99%
Sign Into View Organizational & Contract Pricing