Reversal of drug resistance in Trypanosoma cruzi and Leishmania donovani by verapamil

Neal, R. A.; Bueren, Jacqueline Van; McCoy, Nicholas G.; Iwobi, Mabel

doi:10.1016/0035-9203(89)90642-1

Cited by 54 publications

(37 citation statements)

References 4 publications

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“…Verapamil had been reported earlier to inhibit the efflux of drugs through ABC transporters (20). Similar inhibitory effects of verapamil had also been found in Trypanosoma and laboratory-derived resistant L. donovani isolates (43). In our study, we have found that verapamil (an inhibitor of MDR1) partially reverses the AmB resistance phenotype, a result which has been demonstrated by partial inhibition of AmB efflux (Fig.…”

Section: Discussionsupporting

confidence: 88%

“…Earlier studies have demonstrated that if AmB-induced cell damage is related to generation of ROS (41), the cell's resistance to damage might depend on its ability to decompose them efficiently (4, 7). It had earlier been reported that kinetoplastids detoxify hydroperoxides mainly by the tryparedoxin pathway (39,43). To investigate the involvement of the tryparedoxin cascade in ROS scavenging, the expression levels of different thiol metabolic pathway genes were investigated in both resistant and sensitive parasites.…”

Section: Discussionmentioning

confidence: 99%

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Mechanism of Amphotericin B Resistance in Clinical Isolates of Leishmania donovani

Purkait¹,

Kumar²,

Nandi

et al. 2012

Antimicrob Agents Chemother

273

251

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The clinical value of amphotericin B, the mainstay therapy for visceral leishmaniasis in sodium antimony gluconatenonresponsive zones of Bihar, India, is now threatened by the emergence of acquired drug resistance, and a comprehensive understanding of the underlying mechanisms is the need of the hour. We have selected an amphotericin B-resistant clinical isolate which demonstrated 8-fold-higher 50% lethal doses (LD 50 ) than an amphotericin B-sensitive strain to explore the mechanism of amphotericin B resistance. Fluorimetric analysis demonstrated lower anisotropy in the motion of the diphenylhexatriene fluorescent probe in the resistant strain, which indicated a higher fluidity of the membrane for the resistant strain than for the sensitive strain. The expression patterns of the two transcripts of S-adenosyl-L-methionine:C-24-⌬-sterol methyltransferase and the absence of ergosterol, replaced by cholesta-5,7,24-trien-3␤-ol in the membrane of the resistant parasite, indicate a decreased amphotericin B affinity, which is evidenced by decreased amphotericin B uptake. The expression level of MDR1 is found to be higher in the resistant strain, suggesting a higher rate of efflux of amphotericin B. The resistant parasite also possesses an upregulated tryparedoxin cascade and a more-reduced intracellular thiol level, which helps in better scavenging of reactive oxygen species produced by amphotericin B. The resistance to amphotericin B was partially reverted by the thiol metabolic pathway and ABC transporter inhibitors. Thus, it can be concluded that altered membrane composition, ATP-binding cassette transporters, and an upregulated thiol metabolic pathway have a role in conferring amphotericin B resistance in clinical isolates of Leishmania donovani. L eishmaniasis, or kala azar, is a group of diseases caused by a protozoan parasite of the genus Leishmania. Kala azar is a symptomatic infection of liver, spleen, and bone marrow. The global estimates for the incidence and prevalence of kala azar cases per year are 0.5 and 2.5 million, respectively (57). In India, visceral leishmaniasis (VL) has been reported in parts of West Bengal, Uttar Pradesh, and Bihar. It poses a major health problem in the state of Bihar, which accounts for nearly 90% of the total cases in India (51). Chemotherapy has proven to be the only effective way of controlling infections and is highly dependent upon antimonycontaining drugs, such as sodium stibogluconate (Pentostam). Amphotericin B (AmB) is used as the drug of choice when acquired drug resistance emerges for traditional antimony therapy, and nearly 64% of cases in regions of Bihar where VL is hyperendemic are now resistant to antimonials (28). Hexadecylphosphocholine (miltefosine) is the first orally administered drug for VL and the latest to enter the market. The dosing scheme of hexadecylphosphocholine is 100 mg/kg of body weight/day for 28 days in adults weighing Ն50 kg, 50 mg/kg/day in adults weighing Ͻ50 kg, and 2.5 mg/kg/day in children (maximum dose, 100 mg/day). Major concerns abou...

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Mechanism of Amphotericin B Resistance in Clinical Isolates of Leishmania donovani

Purkait¹,

Kumar²,

Nandi

et al. 2012

Antimicrob Agents Chemother

273

251

View full text Add to dashboard Cite

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“…As has been noted with first-line drugs, verapamil might reduce the macrophage-induced drug tolerance to bedaquiline (4). As in other organisms (17,18), verapamil may prevent the emergence of further drug resistance and thus preserve the activity of bedaquiline. Given the extremely low MIC values achieved with the combination of bedaquiline and verapamil, a drug regimen containing these two agents may be highly effective for the treatment of both drug-resistant and drug-susceptible M. tuberculosis strains.…”

mentioning

confidence: 73%

Efflux Inhibition with Verapamil Potentiates Bedaquiline in Mycobacterium tuberculosis

Gupta

Cohen

Winglee³

et al. 2014

Antimicrob Agents Chemother

149

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Drug efflux is an important resistance mechanism in Mycobacterium tuberculosis. We found that verapamil, an efflux inhibitor, profoundly decreases the MIC of bedaquiline and clofazimine to M. tuberculosis by 8-to 16-fold. This exquisite susceptibility was noted among drug-susceptible and drug-resistant clinical isolates. Thus, efflux inhibition is an important sensitizer of bedaquiline and clofazimine, and efflux may emerge as a resistance mechanism to these drugs.

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“…In addition, it has been shown that macrophage-induced M. tuberculosis tolerance persists after lysis of macrophages; this mechanism is potentially important for bacterial tolerance in the necrotic caseum, where bacilli may be extracellular (4). In addition to its potential role as an antimycobacterial agent, verapamil has been previously shown to block the acquisition of drug resistance in Trypanosoma cruzi and Leishmania donovani (30), and chloroquine resistance in Plasmodium falciparum (31). Verapamil was recently shown to restore susceptibility toward first-line anti-TB drugs in mice infected with a multidrug-resistant M. tuberculosis strain (9).…”

Section: Discussionmentioning

confidence: 99%

Acceleration of Tuberculosis Treatment by Adjunctive Therapy with Verapamil as an Efflux Inhibitor

Gupta

Tyagi

Almeida

et al. 2013

Am J Respir Crit Care Med

152

124

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Rationale: A major priority in tuberculosis (TB) is to reduce effective treatment times and emergence of resistance. Recent studies in macrophages and zebrafish show that inhibition of mycobacterial efflux pumps with verapamil reduces the bacterial drug tolerance and may enhance drug efficacy. Objectives: Using mice, a mammalian model known to predict human treatment responses, and selecting conservative human bioequivalent doses, we tested verapamil as an adjunctive drug together with standard TB chemotherapy. As verapamil is a substrate for CYP3A4, which is induced by rifampin, we evaluated the pharmacokinetic/ pharmacodynamic relationships of verapamil and rifampin coadministration in mice. Methods: Using doses that achieve human bioequivalent levels matched to those of standard verapamil, but lower than those of extended release verapamil, we evaluated the activity of verapamil added to standard chemotherapy in both C3HeB/FeJ (which produce necrotic granulomas) and the wild-type background C3H/HeJ mouse strains. Relapse rates were assessed after 16, 20, and 24 weeks of treatment in mice. Measurements and Main Results: We determined that a dose adjustment of verapamil by 1.5-fold is required to compensate for concurrent use of rifampin during TB treatment. We found that standard TB chemotherapy plus verapamil accelerates bacterial clearance in C3HeB/FeJ mice with near sterilization, and significantly lowers relapse rates in just 4 months of treatment when compared with mice receiving standard therapy alone.Conclusions: These data demonstrate treatment shortening by verapamil adjunctive therapy in mice, and strongly support further study of verapamil and other efflux pump inhibitors in human TB.Keywords: human equivalent doses; verapamil; efflux; Mycobacterium tuberculosis Tuberculosis (TB), a disease affecting millions of people worldwide, requires treatment of patients with multiple drugs for several months. The complexity and length of therapy has led to the emergence of extensively drug-resistant Mycobacterium tuberculosis, which poses a global threat (1). The limited number of new antimicrobials in the TB drug development pipeline further emphasizes the need for fresh approaches in TB therapy. Repurposing existing approved drugs that may serve as treatmentshortening adjuvants is a promising and relatively efficient approach (2). Efflux pump inhibitors (EPIs) are potential agents in this category, and there have been initial promising reports for licensed agents, such as verapamil, reserpine, and piperine (3).Recently, Adams and colleagues (4) showed that the bacterial efflux pump-encoding gene, Rv1258c promotes intracellular bacterial survival, and may mediate drug tolerance. Addition of verapamil reduced tolerance to rifampin in both M. tuberculosis and Mycobacterium marinum, and incubation of M. marinuminfected macrophages with verapamil reduced intracellular bacterial growth. When verapamil was added to isoniazidand rifampin-treated M. marinum-infected macrophages, it restored antibiotic killing by red...

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Reversal of drug resistance in Trypanosoma cruzi and Leishmania donovani by verapamil

Cited by 54 publications

References 4 publications

Mechanism of Amphotericin B Resistance in Clinical Isolates of Leishmania donovani

Mechanism of Amphotericin B Resistance in Clinical Isolates of Leishmania donovani

Efflux Inhibition with Verapamil Potentiates Bedaquiline in Mycobacterium tuberculosis

Acceleration of Tuberculosis Treatment by Adjunctive Therapy with Verapamil as an Efflux Inhibitor

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