The emerging role of amiodarone and dronedarone in Chagas disease

Benaím, Gustavo; Mondolfi, Alberto E. Paniz

doi:10.1038/nrcardio.2012.108

Cited by 60 publications

(52 citation statements)

References 32 publications

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“…Similar results were obtained with amiodarone and dronedarone in T. cruzi and L. mexicana (1)(2)(3)(4)(5). Here, as shown in Fig.…”

supporting

confidence: 77%

“…In the presence of 2 mM external Ca 2ϩ , the same amount of Ca 2ϩ is released by SQ109 (as determined using fura 2) as in the absence of external Ca 2ϩ (i.e., in the presence of 8 mM ethylene glycol tetraacetic acid [EGTA], a highaffinity Ca 2ϩ -specific chelator), which means that it is not the external Ca 2ϩ that is involved in the increase in Ca 2ϩ i . Rather, Ca 2ϩ is released from internal stores, mitochondria and acidocalcisomes, again, just as found for T. cruzi and L. mexicana with amiodarone and dronedarone (1)(2)(3)(4)(5). This disruption of Ca 2ϩ homeostasis in addition to the effects on the proton motive force (as seen also in mycobacteria [10][11][12]) are likely to make major contributions to L. mexicana cell killing.…”

mentioning

confidence: 99%

“…In previous work (1)(2)(3)(4)(5), we discovered that the antiarrhythmia drugs amiodarone (Fig. 1, compound 1) and dronedarone ( Fig.…”

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confidence: 99%

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Inhibition of Leishmania mexicana Growth by the Tuberculosis Drug SQ109

García-García

Oldfield

Benaím

2016

Antimicrob Agents Chemother

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We report that the tuberculosis drug SQ109 [N-adamantan-2-yl-N=-((E)-3,7-dimethyl-octa-2,6-dienyl)-ethane-1,2-diamine] has potent activity against the intracellular amastigote form of Leishmania mexicana (50% inhibitory concentration [IC 50 ], ϳ11 nM), with a good selectivity index (>500). It is also active against promastigotes (IC 50 , ϳ500 nM) and acts as a protonophore uncoupler, in addition to disrupting Ca 2؉ homeostasis by releasing organelle Ca 2؉ into the cytoplasm, and as such, it is an interesting new leishmaniasis drug hit candidate. There is a need for new drugs to treat the neglected tropical diseases, in particular, Chagas disease and leishmaniasis. In previous work (1-5), we discovered that the antiarrhythmia drugs amiodarone (Fig. 1, compound 1) and dronedarone ( Fig. 1, compound 2) had activity against Trypanosoma cruzi as well as Leishmania mexicana, the causative agents of Chagas disease and one form of cutaneous leishmaniasis, respectively. In addition, amiodarone was found to have partial in vivo activity against T. cruzi in mice, which was considerably increased when added in combination with posaconazole (1), and in initial clinical work in humans, it has been used to treat parasitic infections (6, 7). The mechanism of action of compounds 1 and 2 is thought to involve uncoupling activity, with the release of Ca 2ϩ from intracellular organelles (acidocalcisomes and mitochondria), as well as inhibition of oxidosqualene synthase and hence, ergosterol biosynthesis. Interestingly, another type of uncoupler, the nitrothiazole nitazoxanide ( Fig. 1, compound 3), and its active metabolite, tizoxanide ( Fig. 1, compound 4), also have activity against T. cruzi and L. mexicana (8), and compound 4 has been shown to act, at least in part, as an uncoupler, in Mycobacterium tuberculosis (9).Since we and others recently reported (10-13) that another M. tuberculosis drug/drug lead (13-15), SQ109 (Fig. 1, compound 5) [N-adamantan-2-yl-N=-((E)-3,7-dimethyl-octa-2,6-dienyl)-ethane-1,2-diamine], also acted as an uncoupler in Mycobacterium smegmatis, we tested it against T. cruzi, finding 50% inhibitory concentrations (IC 50 s) of ϳ50 nM against trypomastigotes, ϳ5 M against epimastigotes, and ϳ1 M against amastigotes (13). The amastigote result was disappointing, being less effective than that we found with dronedarone (ϳ1 nM); however, since both amiodarone (Cordarone) and dronedarone (Multaq) come with "black box" warnings, we elected to test SQ109 against L. mexicana, since it seemed possible that it might have good activity against this parasitic protozoan, much in the same way as it does against M. tuberculosis (and M. smegmatis).We show in Fig. 2A and B the effects of SQ109 on the viability of L. mexicana promastigotes and intracellular amastigotes (inside J774 macrophages) and on macrophage viability (Fig. 2C and D). As can be seen in Fig. 2A and B, SQ109 inhibits the viability of L. mexicana promastigotes in a dose-dependent manner, and as shown in Fig. 2B, the IC 50 (after 72 h of treatment) is 0....

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“…Similar results were obtained with amiodarone and dronedarone in T. cruzi and L. mexicana (1)(2)(3)(4)(5). Here, as shown in Fig.…”

supporting

confidence: 77%

mentioning

confidence: 99%

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Inhibition of Leishmania mexicana Growth by the Tuberculosis Drug SQ109

García-García

Oldfield

Benaím

2016

Antimicrob Agents Chemother

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“…We found with SQ109 and its analogs that the most potent M. tuberculosis cell growth inhibitors investigated did indeed collapse pH gradients and Δψ, as also observed with the lipophilic bases amiodarone (4) (14) and dronedarone (5) (15), antiarrhythmia drugs, in trypanosomatid parasites (18), and SQ109 (2) also acts as an uncoupler in Trypanosoma cruzi (19). Amiodarone (4) and dronedarone (5) had little uncoupling activity against host cells.…”

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confidence: 88%

Antiinfectives targeting enzymes and the proton motive force

Feng

Zhu

Schurig-Briccio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

148

169

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There is a growing need for new antibiotics. Compounds that target the proton motive force (PMF), uncouplers, represent one possible class of compounds that might be developed because they are already used to treat parasitic infections, and there is interest in their use for the treatment of other diseases, such as diabetes. Here, we tested a series of compounds, most with known antiinfective activity, for uncoupler activity. Many cationic amphiphiles tested positive, and some targeted isoprenoid biosynthesis or affected lipid bilayer structure. As an example, we found that clomiphene, a recently discovered undecaprenyl diphosphate synthase inhibitor active against Staphylococcus aureus, is an uncoupler. Using in silico screening, we then found that the anti-glioblastoma multiforme drug lead vacquinol is an inhibitor of Mycobacterium tuberculosis tuberculosinyl adenosine synthase, as well as being an uncoupler. Because vacquinol is also an inhibitor of M. tuberculosis cell growth, we used similarity searches based on the vacquinol structure, finding analogs with potent (∼0.5-2 μg/mL) activity against M. tuberculosis and S. aureus. Our results give a logical explanation of the observation that most new tuberculosis drug leads discovered by phenotypic screens and genome sequencing are highly lipophilic (logP ∼5.7) bases with membrane targets because such species are expected to partition into hydrophobic membranes, inhibiting membrane proteins, in addition to collapsing the PMF. This multiple targeting is expected to be of importance in overcoming the development of drug resistance because targeting membrane physical properties is expected to be less susceptible to the development of resistance.T here is a need for new antibiotics, due to the increase in drug resistance (1, 2). For example, some studies report that by 2050, absent major improvements in drug discovery and use, more individuals will die from drug-resistant bacterial infections than from cancer, resulting in a cumulative effect on global gross domestic product of as much as 100 trillion dollars (3, 4). To discover new drugs, new targets, leads, concepts, and implementations are needed (5, 6).Currently, one major cause of death from bacterial infections is tuberculosis (TB) (7), where very highly drug-resistant strains have been found (8). Therapy is lengthy, even with drug-sensitive strains, and requires combination therapies with four drugs. Two recent TB drugs/drug leads (9-11) are TMC207 [bedaquiline (1); Sirturo] and SQ109 (2) (Fig. 1). Bedaquiline (1) targets the Mycobacterium tuberculosis ATP synthase (9) whereas SQ109 (2) has been proposed to target MmpL3 (mycobacterial membrane protein large 3), a trehalose monomycolate transporter essential for cell wall biosynthesis (12). SQ109 (2) is a lipophilic base containing an adamantyl "headgroup" connected via an ethylene diamine "linker" to a geranyl (C 10 ) "side chain," and in recent work (13), we synthesized a series of 11 analogs of SQ109 (2) finding that the ethanolamine (3) was more potent th...

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“…Similar results were later found with Leishmania spp. (8,9), and amiodarone is now used clinically for the treatment of chronic Chagas disease (10) and disseminated cutaneous leishmaniasis (11), as discussed in a recent review (12).…”

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SQ109, a New Drug Lead for Chagas Disease

Veiga-Santos

Lameira

et al. 2015

Antimicrob Agents Chemother

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We tested the antituberculosis drug SQ109, which is currently in advanced clinical trials for the treatment of drug-susceptible and drug-resistant tuberculosis, for its in vitro activity against the trypanosomatid parasite Trypanosoma cruzi, the causative agent of Chagas disease. SQ109 was found to be a potent inhibitor of the trypomastigote form of the parasite, with a 50% inhibitory concentration (IC 50 ) for cell killing of 50 ؎ 8 nM, but it had little effect (50% effective concentration [EC 50 ], ϳ80 M) in a red blood cell hemolysis assay. It also inhibited extracellular epimastigotes (IC 50 , 4.6 ؎ 1 M) and the clinically relevant intracellular amastigotes (IC 50 , ϳ0.5 to 1 M), with a selectivity index of ϳ10 to 20. SQ109 caused major ultrastructural changes in all three life cycle forms, as observed by light microscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). It rapidly collapsed the inner mitochondrial membrane potential (⌬ m ) in succinate-energized mitochondria, acting in the same manner as the uncoupler FCCP [carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone], and it caused the alkalinization of internal acidic compartments, effects that are likely to make major contributions to its mechanism of action. The compound also had activity against squalene synthase, binding to its active site; it inhibited sterol side-chain reduction and, in the amastigote assay, acted synergistically with the antifungal drug posaconazole, with a fractional inhibitory concentration index (FICI) of 0.48, but these effects are unlikely to account for the rapid effects seen on cell morphology and cell killing. SQ109 thus most likely acts, at least in part, by collapsing ⌬/⌬pH, one of the major mechanisms demonstrated previously for its action against Mycobacterium tuberculosis. Overall, the results suggest that SQ109, which is currently in advanced clinical trials for the treatment of drug-susceptible and drug-resistant tuberculosis, may also have potential as a drug lead against Chagas disease.

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The emerging role of amiodarone and dronedarone in Chagas disease

Cited by 60 publications

References 32 publications

Inhibition of Leishmania mexicana Growth by the Tuberculosis Drug SQ109

Inhibition of Leishmania mexicana Growth by the Tuberculosis Drug SQ109

Antiinfectives targeting enzymes and the proton motive force

SQ109, a New Drug Lead for Chagas Disease

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