Something Old, Something New: Ion Channel Blockers as Potential Anti-Tuberculosis Agents

Mitini-Nkhoma, Steven C; Chimbayo, Elizabeth; Mzinza, David; Mhango, David V.; Chirambo, Aaron P; Mandalasi, Christine; Lakudzala, Agness; Tembo, Dumizulu; Jambo, Kondwani; Mwandumba, Henry C.

doi:10.3389/fimmu.2021.665785

Cited by 10 publications

(13 citation statements)

References 96 publications

(110 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ion channel blockers are one of the most promising potential HDTs against TB. [57] The fusion of lysosome with autophagosome is the defense mechanism against Mtb. Acidification of the auto phagolysosome prevents the growth of Mtb.…”

Section: Host-directed Therapymentioning

confidence: 99%

Novel Approaches for the Treatment of Drug-Resistant Tuberculosis

Pushkar¹,

Varshney²,

Pushkar³

et al. 2023

Pharmacogn. Res.

View full text Add to dashboard Cite

Tuberculosis (TB) is a leading infectious disease that caused the deaths of a total of 1.5 million people in 2020 and is one of the top causes of death globally. India is a country with the highest TB burden, and it may affect all age groups. It is caused by the Mycobacterium tuberculosis bacteria, an intracellular pathogen, and its multidrug and extensively drug-resistant strains, which continue to emerge and spread, resulting in the deadliest infectious disease. After a gap of more than 40 years, the FDA approvals over the past decade of three second-line anti-TB drugs, bedaquiline, delamanid, and pretomanid, have been major forward steps in the management of drug-resistant-TB (DR-TB). Many medicinal plants such as Zanthoxylum leprieurii, Lantana camara, and Cryptolepis sanguinolenta have extensive therapeutic potential and represent a prospective option to fight against DR-TB. Some novel compounds are in the early clinical trial phases such as DprE1 inhibitors TBA-7371 and BTZ-043, and many others that are showing promising futures. This review describes DR-TB and its current chemotherapy guidelines including novel and repurposed drugs that are included in the anti-TB regimens, medicinal plants that have therapeutic potential for the development of drug-hit candidates, drugs that are currently in clinical development, host-directed therapy, and new drug delivery systems to better understand the novel therapeutic approaches that are currently being studied for the efficacious and safe management of DR-TB, a worldwide health problem.

show abstract

Section: Host-directed Therapymentioning

confidence: 99%

Novel Approaches for the Treatment of Drug-Resistant Tuberculosis

Pushkar¹,

Varshney²,

Pushkar³

et al. 2023

Pharmacogn. Res.

View full text Add to dashboard Cite

show abstract

“…Another strategy is to aim at host ion channels, that orchestrate physiological features of various cell populations by operating ions facilitated currents throughout cellular and subcellular membranes ( 143 ). Intracellular calcium levels are known to regulate key immune responses in the host, directly or by directional alteration of other vital ions such as potassium (K + ), sodium (Na + ), and chloride (Cl - ) ions within immune cell populations ( 144 ).…”

Section: Targeting Host Ion Channelsmentioning

confidence: 99%

“…So as to bypass host immune responses M.tb upregulates the expression of VGCCs in APCs. Verapamil administration inhibits LTCC currents thereby escalating Ca 2+ concentration in the cytosol which upregulates autophagy and bacterial clearance in M.tb ( 143 ). Additionally, LTCC ion channel blockers can alter iron-associated metabolic pathways thereby impeding iron accessibility which lowers intracellular bacterial survival ( 143 ).…”

Section: Targeting Host Ion Channelsmentioning

confidence: 99%

“…Verapamil administration inhibits LTCC currents thereby escalating Ca 2+ concentration in the cytosol which upregulates autophagy and bacterial clearance in M.tb ( 143 ). Additionally, LTCC ion channel blockers can alter iron-associated metabolic pathways thereby impeding iron accessibility which lowers intracellular bacterial survival ( 143 ). Furthermore, verapamil acts synergistically with first-line anti-TB drugs- INH ( 152 ), and RIF ( 153 ) in lowering the bacterial burden in cultures, macrophages, and murine models of TB.…”

Section: Targeting Host Ion Channelsmentioning

confidence: 99%

See 1 more Smart Citation

Progressive Host-Directed Strategies to Potentiate BCG Vaccination Against Tuberculosis

2022

View full text Add to dashboard Cite

The pursuit to improve the TB control program comprising one approved vaccine, M. bovis Bacille Calmette-Guerin (BCG) has directed researchers to explore progressive approaches to halt the eternal TB pandemic. Mycobacterium tuberculosis (M.tb) was first identified as the causative agent of TB in 1882 by Dr. Robert Koch. However, TB has plagued living beings since ancient times and continues to endure as an eternal scourge ravaging even with existing chemoprophylaxis and preventive therapy. We have scientifically come a long way since then, but despite accessibility to the standard antimycobacterial antibiotics and prophylactic vaccine, almost one-fourth of humankind is infected latently with M.tb. Existing therapeutics fail to control TB, due to the upsurge of drug-resistant strains and increasing incidents of co-infections in immune-compromised individuals. Unresponsiveness to established antibiotics leaves patients with no therapeutic possibilities. Hence the search for an efficacious TB immunization strategy is a global health priority. Researchers are paving the course for efficient vaccination strategies with the radically advanced operation of core principles of protective immune responses against M.tb. In this review; we have reassessed the progression of the TB vaccination program comprising BCG immunization in children and potential stratagems to reinforce BCG-induced protection in adults.

show abstract

“…However, eliminating persistent and drug-tolerant subpopulations requires prolonged treatment ( Sebastian et al, 2022 ). The differential sensitivity of MTB to drugs is determined, at least in part, by the interaction between the bacilli and the various macrophage populations of the host ( Mitini-Nkhoma et al, 2021 ). Therefore, to design better treatment regimens for TB, we must understand the heterogeneity and modulate the divergent responses of MTB bacilli within macrophages ( Mitini-Nkhoma et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Effect of calcium-channel blockers on the risk of active tuberculosis and mortality: systematic review and meta-analysis

Meregildo-Rodriguez,

Asmat-Rubio,

Bardales-Zuta

et al. 2024

Front. Pharmacol.

View full text Add to dashboard Cite

Introduction: Recent studies suggest that calcium channel blockers (CCBs) could reduce the risk of active tuberculosis and improve clinical outcomes. We aimed to synthesize the evidence regarding the effect of CCBs on the risk of developing active tuberculosis and mortality.Methods: We systematically searched for observational studies and clinical trials published in six databases until 31 August 2023, following a PECO/PICO strategy.Results: We included eight observational studies, 4,020,830 patients, among whom 241,761 had diabetes mellitus and 30,397 had active tuberculosis. According to our results, CCBs reduce the risk of developing active tuberculosis by 29% (RR 0.71; 95% CI 0.67–0.75) in patients with and without diabetes mellitus. However, CCBs do not show any benefit in terms of tuberculosis-related mortality (RR 1.00; 95% CI 0.98–1.02). For both outcomes, no statistical heterogeneity was found (I2 = 0, p > 0.10). This protective effect of CCBs on the risk of active tuberculosis remained independent of the type of patient (with diabetes mellitus vs. general population) or the class of CCB administered (DHP-CCB vs. non-DHP-CCB) (test for subgroup differences I2 = 0, p > 0.10). However, this beneficial effect was more significant among the general population (RR 0.70; 95% CI 0.66–0.74) compared to patients with diabetes mellitus (RR 0.72; 95% CI 0.61–0.86) and among those patients treated with DHP-CCBs (RR 0.69; 95% CI 0.63–0.74) compared to patients treated with non-DHP-CCBs (RR 0.72; 95% CI 0.67–0.78).Conclusion: CCBs may reduce the risk of active TB in patients with diabetes and the general population. On the contrary, CCBs do not seem to have a protective effect on tuberculosis-related mortality. However, more evidence is still needed. We recommend developing clinical trials to verify these findings, including more diverse populations.Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=352129]

show abstract

Something Old, Something New: Ion Channel Blockers as Potential Anti-Tuberculosis Agents

Cited by 10 publications

References 96 publications

Novel Approaches for the Treatment of Drug-Resistant Tuberculosis

Novel Approaches for the Treatment of Drug-Resistant Tuberculosis

Progressive Host-Directed Strategies to Potentiate BCG Vaccination Against Tuberculosis

Effect of calcium-channel blockers on the risk of active tuberculosis and mortality: systematic review and meta-analysis

Contact Info

Product

Resources

About