Rational Selection of Anti‐Microbial Drug Targets: Unique or Conserved?

Rodenko, Boris; Koning, Harry P. de

doi:10.1002/9783527670383.ch15

Cited by 4 publications

(5 citation statements)

References 64 publications

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“…2 As current drugs are becoming ineffective due to drug resistance, cross-resistance between existing drugs and new ones is one of the most important issues that must be tackled early in the search for new antitrypanosomal agents. 48 In this work, two trypanocidal scaffolds (i.e. trypanocides 28 , and probably reflects the higher lipophilicity and charge dispersion around the phosphorus atom in the TPP cation, which is optimal for membrane permeation and accumulation in the mitochondrion.…”

Section: Discussionmentioning

confidence: 90%

“…Moreover, drugs against animal African trypanosomiasis (AAT, or nagana) are even more urgently needed than for the corresponding human condition . As current drugs are becoming ineffective due to drug resistance, cross-resistance between existing drugs and new ones is one of the most important issues that must be tackled in the search for new antitrypanosomal agents …”

Section: Discussionmentioning

confidence: 99%

“…2 As current drugs are becoming ineffective due to drug resistance, cross-resistance between existing drugs and new ones is one of the most important issues that must be tackled in the search for new antitrypanosomal agents. 48 In this work, two trypanocidal scaffolds (i.e., 2,4-dihydroxybenzoic acid and salicylhydroxamic acid) known to interact with mitochondrial targets 9,12,17 were conjugated with one of two mitochondrion-targeting lipophilic cations in order to boost their potency against trypanosomes. The activities against WT and multidrug-resistant T. brucei strains and against a T. congolense strain were studied in vitro.…”

Section: ■ Discussionmentioning

confidence: 99%

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Conjugates of 2,4-Dihydroxybenzoate and Salicylhydroxamate and Lipocations Display Potent Antiparasite Effects by Efficiently Targeting the Trypanosoma brucei and Trypanosoma congolense Mitochondrion

et al. 2017

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We investigated a chemical strategy to boost the trypanocidal activity of 2,4dihydroxybenzoic acid (2,4-DHBA)-and salicylhydroxamic acid (SHAM)-based trypanocides with triphenylphosphonium and quinolinium lipophilic cations (LC). Three series of LC conjugates were synthesized that were active in the submicromolar (5a-d and 10d-f) to low nanomolar (6a-f) range against wild-type and multi-drug resistant strains of African trypanosomes (Trypanosoma brucei brucei and T. congolense). This represented an improvement in trypanocidal potency of at least 200fold, and up to >10,000-fold, compared with the non-LC coupled parent compounds 2,4-DHBA and SHAM. Selectivity over human cells was >500 and reached >23,000 for 6e. Mechanistic studies showed that 6e did not inhibit the cell cycle but affected parasite respiration in a dose-dependent manner. Inhibition of the trypanosome alternative oxidase (TAO) and the mitochondrial membrane potential was also studied for selected compounds. We conclude that effective mitochondrial targeting greatly potentiated the activity of these compound series.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

“…2 As current drugs are becoming ineffective due to drug resistance, cross-resistance between existing drugs and new ones is one of the most important issues that must be tackled in the search for new antitrypanosomal agents. 48 In this work, two trypanocidal scaffolds (i.e., 2,4-dihydroxybenzoic acid and salicylhydroxamic acid) known to interact with mitochondrial targets 9,12,17 were conjugated with one of two mitochondrion-targeting lipophilic cations in order to boost their potency against trypanosomes. The activities against WT and multidrug-resistant T. brucei strains and against a T. congolense strain were studied in vitro.…”

Section: ■ Discussionmentioning

confidence: 99%

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Conjugates of 2,4-Dihydroxybenzoate and Salicylhydroxamate and Lipocations Display Potent Antiparasite Effects by Efficiently Targeting the Trypanosoma brucei and Trypanosoma congolense Mitochondrion

et al. 2017

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“…This inhibitor has been shown to reduce the parasitaemia and to prolong the survival of T. brucei-infected mice (Caffrey et al, 2000). Considering that K11777 has been approved by the FDA to enter a phase I safety trial in the United States (Rodenko and de Koning, 2013), the main aim of this study was to evaluate the trypanocidal efficacy of K11777 and anti-HAT drug combinations on bloodstream forms of T. brucei in vitro.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of trypanocidal activity of combinations of anti-sleeping sickness drugs with cysteine protease inhibitors

Steverding

2015

Experimental Parasitology

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Chemotherapy of human African trypanosomiasis (HAT) is unsatisfactory because only a few drugs, with serious side effects and poor efficacy, are available. As drug combination regimes often achieve greater therapeutic efficacy than monotherapies, here the trypanocidal activity of the cysteine protease inhibitor K11777 in combination with current anti-HAT drugs using bloodstream forms of Trypanosoma brucei was investigated. Isobolographic analysis was used to determine the interaction between cysteine protease inhibitors (K11777, CA-074Me and CAA0225) and anti-HAT drugs (suramin, pentamidine, melarsoprol and eflornithine). Bloodstream forms of T. brucei were incubated in culture medium containing cysteine protease inhibitors or anti-HAT drugs alone or in combination at a 1:1 fixed-dose ratio. After 48 h incubation, live cells were counted, the 50% growth inhibition values determined and combination indices calculated. The general cytotoxicity of drug combinations was evaluated with human leukaemia HL-60 cells. Combinations of K11777 with suramin, pentamidine and melarsoprol showed antagonistic effects while with eflornithine a synergistic effect was observed. Whereas eflornithine antagonises with CA-074Me, an inhibitor inactivating the targeted TbCATL only under reducing conditions, it synergises with CAA0255, an inhibitor structurally related to CA-074Me which inactivates TbCATL independently of thiols. These findings indicate an essential role of thiols for the synergistic interaction between K11777 and eflornithine. Encouragingly, the K11777/eflornithine combination displayed higher trypanocidal than cytotoxic activity. The results of this study suggest that the combination of the cysteine protease inhibitor K11777 and eflornithine display promising synergistic trypanocidal activity that warrants further investigation of the drug combination as possible alternative treatment of HAT.

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“…These parasites are known to express ENT family transporters for the uptake of nucleobases and/or nucleosides, which is an essential function because they are unable to synthesize purines de novo, relying on salvage from the host environment [1,8,9]. Due to this dependence on transport, several pharmacological approaches have focused on purine transporters as drug carriers for the treatment of parasitic infections, especially HAT [10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Trypanosoma brucei bloodstream forms express highly specific and separate transporters for adenine and hypoxanthine; evidence for a new protozoan purine transporter family?

Campagnaro

Alzahrani

Munday

et al. 2018

Molecular and Biochemical Parasitology

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Rational Selection of Anti‐Microbial Drug Targets: Unique or Conserved?

Cited by 4 publications

References 64 publications

Conjugates of 2,4-Dihydroxybenzoate and Salicylhydroxamate and Lipocations Display Potent Antiparasite Effects by Efficiently Targeting the Trypanosoma brucei and Trypanosoma congolense Mitochondrion

Conjugates of 2,4-Dihydroxybenzoate and Salicylhydroxamate and Lipocations Display Potent Antiparasite Effects by Efficiently Targeting the Trypanosoma brucei and Trypanosoma congolense Mitochondrion

Evaluation of trypanocidal activity of combinations of anti-sleeping sickness drugs with cysteine protease inhibitors

Trypanosoma brucei bloodstream forms express highly specific and separate transporters for adenine and hypoxanthine; evidence for a new protozoan purine transporter family?

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