Verapamil Suppresses the Development of Resistance Against Anti-Tuberculosis Drugs in Mycobacteria

Liu, Kunna; Buitenhek, Elise; Kuijl, Coenraad P.; Mulla, Yuval; Luirink, Joen; Bald, Dirk

doi:10.3390/ijms262211124

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Open AccessArticle

Verapamil Suppresses the Development of Resistance Against Anti-Tuberculosis Drugs in Mycobacteria

by

Kunna Liu

¹,

Elise Buitenhek

¹,

Coenraad P. Kuijl

^2,3

,

Yuval Mulla

^1,*

,

Joen Luirink

¹ and

Dirk Bald

^1,*

¹

Molecular Microbiology Section, A-LIFE and AIMMS, Faculty of Science, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands

²

Medical Microbiology and Infection Control (MMI), Amsterdam University Medical Center Location VUmc, 1081 HZ Amsterdam, The Netherlands

³

Amsterdam Institute for Immunology & Infectious Diseases, Amsterdam University Medical Center Location VUmc, 1081 HZ Amsterdam, The Netherlands

^*

Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2025, 26(22), 11124; https://doi.org/10.3390/ijms262211124 (registering DOI)

Submission received: 22 October 2025 / Revised: 10 November 2025 / Accepted: 13 November 2025 / Published: 17 November 2025

(This article belongs to the Special Issue Antibiotics Science: Molecular Insights, Detection Strategies, Resistance Challenges and Interdisciplinary Applications)

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Abstract

The emergence of drug resistance remains a major challenge in the treatment of tuberculosis and other mycobacterial infections. To combat the rise in resistance, strategies that reduce the frequency of resistance mutations are urgently needed. Verapamil is a small-molecule compound that can enhance the potency of companion drugs in combination regimen. Here, we investigate if verapamil can decrease the resistance frequency of antimycobacterial drugs. The results show that verapamil significantly reduces the resistance frequency of multiple antimycobacterial agents, including the DNA gyrase inhibitor moxifloxacin, the protein synthesis inhibitor streptomycin, and the RNA polymerase inhibitor rifampicin in Mycobacterium smegmatis. The presence of point mutations in the target was confirmed for moxifloxacin-resistant M. smegmatis. Suppression of resistance evolution against moxifloxacin by verapamil was also found in the slow-growing, pathogenic mycobacteria M. avium and M. tuberculosis. Real-time qPCR analysis in M. smegmatis showed that verapamil treatment downregulates the expression of multiple efflux pump genes and upregulates DNA repair genes. These findings suggest that verapamil exerts a dual role by interfering with efflux pump functionality and by reducing the probability of chromosomal mutations. The combination of these properties may underlie the promise of verapamil as adjuvant to enhance the effectiveness of current antimycobacterial chemotherapy.

Keywords: verapamil; mycobacteria; resistance frequency; efflux pump; DNA repair

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MDPI and ACS Style

Liu, K.; Buitenhek, E.; Kuijl, C.P.; Mulla, Y.; Luirink, J.; Bald, D. Verapamil Suppresses the Development of Resistance Against Anti-Tuberculosis Drugs in Mycobacteria. Int. J. Mol. Sci. 2025, 26, 11124. https://doi.org/10.3390/ijms262211124

AMA Style

Liu K, Buitenhek E, Kuijl CP, Mulla Y, Luirink J, Bald D. Verapamil Suppresses the Development of Resistance Against Anti-Tuberculosis Drugs in Mycobacteria. International Journal of Molecular Sciences. 2025; 26(22):11124. https://doi.org/10.3390/ijms262211124

Chicago/Turabian Style

Liu, Kunna, Elise Buitenhek, Coenraad P. Kuijl, Yuval Mulla, Joen Luirink, and Dirk Bald. 2025. "Verapamil Suppresses the Development of Resistance Against Anti-Tuberculosis Drugs in Mycobacteria" International Journal of Molecular Sciences 26, no. 22: 11124. https://doi.org/10.3390/ijms262211124

APA Style

Liu, K., Buitenhek, E., Kuijl, C. P., Mulla, Y., Luirink, J., & Bald, D. (2025). Verapamil Suppresses the Development of Resistance Against Anti-Tuberculosis Drugs in Mycobacteria. International Journal of Molecular Sciences, 26(22), 11124. https://doi.org/10.3390/ijms262211124

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Verapamil Suppresses the Development of Resistance Against Anti-Tuberculosis Drugs in Mycobacteria

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