ArticleAntimicrobial agents and chemotherapy2015
New Verapamil Analogs Inhibit Intracellular Mycobacteria without Affecting the Functions of Mycobacterium-Specific T Cells.
Article in Antimicrobial agents and chemotherapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 26 citations in OpenAlex.
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- Mab2780c, a TetV-like efflux pump, confers high-level spectinomycin resistance in mycobacterium abscessus.Tuberculosis (Edinburgh, Scotland) · 2023Article
- C-1 Substituted isoquinolines potentiate the antimycobacterial activity of rifampicin and ethambutol.Frontiers in antibiotics · 2023Article
- The CaPharmaceutics · 2022Article
- Strategies to Combat Multi-Drug Resistance in Tuberculosis.Accounts of chemical research · 2021Review
- Autophagy as a Target for Drug Development Of Skin Infection Caused by Mycobacteria.Frontiers in immunology · 2021Review
- Antimicrobial and Efflux Pump Inhibitory Activity of Carvotacetones fromAntibiotics (Basel, Switzerland) · 2020Article
- Flavonoids as Novel Efflux Pump Inhibitors and Antimicrobials Against Both Environmental and Pathogenic Intracellular Mycobacterial Species.Molecules (Basel, Switzerland) · 2020Article
- Ion Transport Modulators as Antimycobacterial Agents.Tuberculosis research and treatment · 2020Article
- Chemical disarming of isoniazid resistance inProceedings of the National Academy of Sciences of the United States of America · 2019Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
There is a growing interest in repurposing mycobacterial efflux pump inhibitors, such as verapamil, for tuberculosis (TB) treatment. To aid in the design of better analogs, we studied the effects of verapamil on macrophages and Mycobacterium tuberculosis-specific T cells. Macrophage activation was evaluated by measuring levels of nitric oxide, tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and gamma interferon (IFN-γ). Since verapamil is a known autophagy inducer, the roles of autophagy induction in the antimycobacterial activities of verapamil and norverapamil were studied using bone marrow-derived macrophages from ATG5(flox/flox) (control) and ATG5(flox/flox) Lyz-Cre mice. Our results showed that despite the well-recognized effects of verapamil on calcium channels and autophagy, its action on intracellular M. tuberculosis does not involve macrophage activation or autophagy induction. Next, the effects of verapamil and norverapamil on M. tuberculosis-specific T cells were assessed using flow cytometry following the stimulation of peripheral blood mononuclear cells from TB-skin-test-positive donors with M. tuberculosis whole-cell lysate for 7 days in the presence or absence of drugs. We found that verapamil and norverapamil inhibit the expansion of M. tuberculosis-specific T cells. Additionally, three new verapamil analogs were found to inhibit intracellular Mycobacterium bovis BCG, and one of the three analogs (KSV21) inhibited intracellular M. tuberculosis replication at concentrations that did not inhibit M. tuberculosis-specific T cell expansion. KSV21 also inhibited mycobacterial efflux pumps to the same degree as verapamil. More interestingly, the new analog enhances the inhibitory activities of isoniazid and rifampin on intracellular M. tuberculosis. In conclusion, KSV21 is a promising verapamil analog on which to base structure-activity relationship studies aimed at identifying more effective analogs.
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