Modulatory Effects of Verapamil in Rifampicin Activity Against
            <i>Mycobacterium Tuberculosis</i>

Caleffi-Ferracioli, Katiany Rizzieri; Cardoso, Rosilene Fressatti; Souza, Joao V. P. de; Murase, Letícia Sayuri; Canezin, Pedro Henrique; Scodro, Regiane Bertin de Lima; Siqueira, Vera Lúcia Dias; Pavan, Fernando Rogério

doi:10.2217/fmb-2018-0277

Cited by 10 publications

(13 citation statements)

References 39 publications

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“…1 to 3). All M. tuberculosis strains (although at a milder response for H 37 Rv) responded to stress caused by RIF through a general increase of EP transcript levels, similarly to results reported in a previous study (4). Relative transcript levels of Rv2942 and Rv1458c were not detected in H 37 Rv in any exposure condition.…”

supporting

confidence: 86%

“…The emergence of anti-TB-drug-resistant M. tuberculosis strains highlights the need for new strategies to deal with TB worldwide. One particular strategy for future therapy is the use of efflux pump inhibitors (EPIs) added to anti-TB drugs (3,4).…”

mentioning

confidence: 99%

“…Our research group has recently published articles on how EPIs might act in synergy with commonly used anti-TB drugs and underlined the manner in which EPIs impact the efflux pump (EP) expression in M. tuberculosis (4)(5)(6)(7). Piperine, which is known to have an efflux-inhibitory activity, has proved to be significantly efficacious as an adjunct drug in TB treatment (8)(9)(10) and has already been tested in a phase III clinical trial in India (11).…”

mentioning

confidence: 99%

“…The control comprised a reference assay conducted without drugs and solvents. Cell lysis, RNA extraction and purification, DNA contamination removal, cDNA synthesis, and reverse transcription quantitative (RT-qPCR) were carried out following the protocol from a previous study (4). Quantitative PCR (qPCR) amplification conditions varied according to EP primers (Promega, USA) ( Table 2).…”

mentioning

confidence: 99%

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Possible Binding of Piperine in Mycobacterium tuberculosis RNA Polymerase and Rifampin Synergism

Murase

Souza

Meneguello

et al. 2019

Antimicrob Agents Chemother

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The activity of rifampin (RIF) and piperine was evaluated at the relative transcript levels of 12 efflux pumps (EPs), and an additional mechanism was proposed to be behind the synergic interactions of piperine plus RIF in Mycobacterium tuberculosis. AutoDock v4.2.3 and Molegro v6 programs were used to evaluate PIP binding in M. tuberculosis RNA polymerase (RNAP). A hypothesis has been raised that piperine interferes in M. tuberculosis growth through RNAP inhibition, differently from what was previously endorsed for EP inhibition only.

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supporting

confidence: 86%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Possible Binding of Piperine in Mycobacterium tuberculosis RNA Polymerase and Rifampin Synergism

Murase

Souza

Meneguello

et al. 2019

Antimicrob Agents Chemother

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“…Gupta et al also suggested that administration of verapamil together with bedaquiline reduces the bacterial load in M.tb infected mice and therefore calcium efflux blockers can be explored as adjuncts in TB therapy (93). After this pioneering work, many follow up studies also confirmed the protective role of verapamil in TB therapy (94)(95)(96). These studies demonstrated other mechanisms of protection conferred by verapamil such as by increasing the bioavailability of bedaquiline (94) and by disturbing the mycobacterial membrane energetics (95).…”

Section: Verapamilmentioning

confidence: 98%

Repurposing Immunomodulatory Drugs to Combat Tuberculosis

2021

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Tuberculosis (TB) is an infectious disease caused by an obligate intracellular pathogen, Mycobacterium tuberculosis (M.tb) and is responsible for the maximum number of deaths due to a single infectious agent. Current therapy for TB, Directly Observed Treatment Short-course (DOTS) comprises multiple antibiotics administered in combination for 6 months, which eliminates the bacteria and prevents the emergence of drug-resistance in patients if followed as prescribed. However, due to various limitations viz., severe toxicity, low efficacy and long duration; patients struggle to comply with the prescribed therapy, which leads to the development of drug resistance (DR). The emergence of resistance to various front-line anti-TB drugs urgently require the introduction of new TB drugs, to cure DR patients and to shorten the treatment course for both drug-susceptible and resistant populations of bacteria. However, the development of a novel drug regimen involving 2-3 new and effective drugs will require approximately 20-30 years and huge expenditure, as seen during the discovery of bedaquiline and delamanid. These limitations make the field of drug-repurposing indispensable and repurposing of pre-existing drugs licensed for other diseases has tremendous scope in anti-DR-TB therapy. These repurposed drugs target multiple pathways, thus reducing the risk of development of drug resistance. In this review, we have discussed some of the repurposed drugs that have shown very promising results against TB. The list includes sulfonamides, sulfanilamide, sulfadiazine, clofazimine, linezolid, amoxicillin/clavulanic acid, carbapenems, metformin, verapamil, fluoroquinolones, statins and NSAIDs and their mechanism of action with special emphasis on their immunomodulatory effects on the host to attain both host-directed and pathogen-targeted therapy. We have also focused on the studies involving the synergistic effect of these drugs with existing TB drugs in order to translate their potential as adjunct therapies against TB.

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