Repurposing topical triclosan for cutaneous leishmaniasis: Preclinical efficacy in a murine Leishmania (L.) amazonensis model

Leishmaniasis remains an important neglected tropical infection caused by the protozoan Leishmania and affects 12 million people in 98 countries. The treatment is limited with severe adverse effects. In the search for new therapies, the drug repositioning and combination therapy have been successfully applied to neglected diseases. The aim of the present study was to evaluate the in vitro and in vivo anti‐Leishmania (Leishmania) amazonensis potential of triclosan, an approved topical antimicrobial agent used for surgical procedures. in vitro phenotypic studies of drug‐treated parasites were performed to evaluate the lethal action of triclosan, accompanied by an isobolographic ex‐vivo analysis with the association of triclosan and miltefosine. The results showed that triclosan has activity against L. (L.) amazonensis intracellular amastigotes, with a 50% inhibitory concentration of 16 μM. By using fluorescent probes and transmission electron microscopy, a pore‐forming activity of triclosan toward the parasite plasma membrane was demonstrated, leading to depolarization of the mitochondrial membrane potential and reduction of the reactive oxygen species levels in the extracellular promastigotes. The in vitro interaction between triclosan and miltefosine in the combination therapy assay was classified as additive against intracellular amastigotes. Leishmania‐infected mice were treated with topical triclosan (1% base cream for 14 consecutive days), and showed 89% reduction in the parasite burden. The obtained results contribute to the investigation of new alternatives for the treatment of cutaneous leishmaniasis and suggest that the coadministration of triclosan and miltefosine should be investigated in animal models.

[1]  Igor Cestari,et al.  The current drug discovery landscape for trypanosomiasis and leishmaniasis: Challenges and strategies to identify drug targets , 2020, Drug development research.

[2]  J. Augereau,et al.  Design, Synthesis and Efficacy of Hybrid Triclosan‐gold Based Molecules on Artemisinin‐resistant Plasmodium falciparum and Leishmania infantum Parasites , 2020, ChemistrySelect.

[3]  Ross D. King,et al.  Plasmodium dihydrofolate reductase is a second enzyme target for the antimalarial action of triclosan , 2018, Scientific Reports.

[4]  L. Leon,et al.  Leishmaniasis treatment: update of possibilities for drug repurposing. , 2018, Frontiers in bioscience.

[5]  S. Robledo,et al.  Triclosan-caffeic acid hybrids: Synthesis, leishmanicidal, trypanocidal and cytotoxic activities. , 2017, European journal of medicinal chemistry.

[6]  G. Wynne,et al.  Efficacy of a series of alpha-pyrone derivatives against Leishmania (L.) infantum and Trypanosoma cruzi. , 2017, European journal of medicinal chemistry.

[7]  S. Sundar,et al.  Voacamine alters Leishmania ultrastructure and kills parasite by poisoning unusual bi‐subunit topoisomerase IB , 2017, Biochemical pharmacology.

[8]  P. Denny,et al.  Repurposing as a strategy for the discovery of new anti-leishmanials: the-state-of-the-art , 2017, Parasitology.

[9]  R. Arenas,et al.  Leishmaniasis: a review , 2017, F1000Research.

[10]  T. Rosenau,et al.  Mechanism of ascaridole activation in Leishmania , 2017, Biochemical pharmacology.

[11]  Cristiana T. Trinconi,et al.  Chemotherapy of leishmaniasis: present challenges , 2017, Parasitology.

[12]  M. Doležal,et al.  Enoyl acyl carrier protein reductase inhibitors: an updated patent review (2011 – 2015) , 2016, Expert opinion on therapeutic patents.

[13]  Cristiana T. Trinconi,et al.  Efficacy of tamoxifen and miltefosine combined therapy for cutaneous leishmaniasis in the murine model of infection with Leishmania amazonensis. , 2016, The Journal of antimicrobial chemotherapy.

[14]  R. J. Alves,et al.  An effective in vitro and in vivo antileishmanial activity and mechanism of action of 8-hydroxyquinoline against Leishmania species causing visceral and tegumentary leishmaniasis. , 2016, Veterinary parasitology.

[15]  R. Tukey,et al.  Triclosan: A Widespread Environmental Toxicant with Many Biological Effects. , 2016, Annual review of pharmacology and toxicology.

[16]  V. Ferrières,et al.  Leishmania cell wall as a potent target for antiparasitic drugs. A focus on the glycoconjugates. , 2015, Organic & biomolecular chemistry.

[17]  H. Ramadan,et al.  Triclosan and triclosan-loaded liposomal nanoparticles in the treatment of acute experimental toxoplasmosis. , 2015, Experimental parasitology.

[18]  S. Robledo,et al.  Synthesis, Leishmanicidal and Cytotoxic Activity of Triclosan-Chalcone, Triclosan-Chromone and Triclosan-Coumarin Hybrids , 2014, Molecules.

[19]  T. A. da Costa-Silva,et al.  Activity of imidazole compounds on Leishmania (L.) infantum chagasi: reactive oxygen species induced by econazole , 2013, Molecular and Cellular Biochemistry.

[20]  N. Taniwaki,et al.  Lethal action of the nitrothiazolyl-salicylamide derivative nitazoxanide via induction of oxidative stress in Leishmania (L.) infantum. , 2013, Acta tropica.

[21]  H. F. de Andrade,et al.  Biodistribution of meglumine antimoniate in healthy and Leishmania (Leishmania) infantum chagasi-infected BALB/c mice , 2013, Memorias do Instituto Oswaldo Cruz.

[22]  Cristiana T. Trinconi,et al.  Parasite burden in Leishmania (Leishmania) amazonensis-infected mice: validation of luciferase as a quantitative tool. , 2013, Journal of microbiological methods.

[23]  T. C. White,et al.  Triclosan Antagonizes Fluconazole Activity against Candida albicans , 2012, Journal of dental research.

[24]  A. Tempone,et al.  Investigation into in vitro anti-leishmanial combinations of calcium channel blockers and current anti-leishmanial drugs. , 2011, Memorias do Instituto Oswaldo Cruz.

[25]  D. Muñoz,et al.  Synthesis and leishmanicidal activity of quinoline–triclosan and quinoline–eugenol hybrids , 2011, Medicinal Chemistry Research.

[26]  D. C. Miguel Caracterização da atividade de tamoxifeno no tratamento da leishmaniose experimental e investigação sobre seus mecanismos de ação. , 2011 .

[27]  N. Alexander,et al.  Safety and Efficacy of miltefosine alone and in combination with sodium stibogluconate and liposomal amphotericin B for the treatment of primary visceral leishmaniasis in East Africa: study protocol for a randomized controlled trial , 2011, Trials.

[28]  Xuming Deng,et al.  In Vitro Interaction between Fluconazole and Triclosan against Clinical Isolates of Fluconazole-Resistant Candida albicans Determined by Different Methods , 2011, Antimicrobial Agents and Chemotherapy.

[29]  E. E. Almeida-Amaral,et al.  Reactive Oxygen Species Production and Mitochondrial Dysfunction Contribute to Quercetin Induced Death in Leishmania amazonensis , 2011, PloS one.

[30]  Bhavna Chawla,et al.  Drug targets in Leishmania , 2010, Journal of parasitic diseases : official organ of the Indian Society for Parasitology.

[31]  J. Wohlrab,et al.  Antiseptic Efficacy of a Low-Dosed Topical Triclosan/Chlorhexidine Combination Therapy in Atopic Dermatitis , 2006, Skin Pharmacology and Physiology.

[32]  D. Warhurst,et al.  Modified Fixed-Ratio Isobologram Method for Studying In Vitro Interactions between Atovaquone and Proguanil or Dihydroartemisinin against Drug-Resistant Strains of Plasmodium falciparum , 2004, Antimicrobial Agents and Chemotherapy.

[33]  F. Odds,et al.  Synergy, antagonism, and what the chequerboard puts between them. , 2003, The Journal of antimicrobial chemotherapy.

[34]  H. Schweizer Triclosan: a widely used biocide and its link to antibiotics. , 2001, FEMS microbiology letters.

[35]  C. Mateo,et al.  Membranotropic effects of the antibacterial agent Triclosan. , 2001, Archives of biochemistry and biophysics.

[36]  R. Lyons,et al.  Triclosan inhibits the growth of Plasmodium falciparum and Toxoplasma gondii by inhibition of apicomplexan Fab I. , 2001, International journal for parasitology.

[37]  V. Yardley,et al.  A comparison of the activities of three amphotericin B lipid formulations against experimental visceral and cutaneous leishmaniasis. , 2000, International journal of antimicrobial agents.

[38]  J. Chalmers,et al.  The importance of drug combinations for effective control of hypertension. , 1999, Clinical and experimental hypertension.

[39]  J. Berman,et al.  Successful topical treatment of murine cutaneous leishmaniasis with a combination of paromomycin (Aminosidine) and gentamicin. , 1999, The Journal of parasitology.

[40]  Antoni R. Slabas,et al.  Molecular basis of triclosan activity , 1999, Nature.

[41]  I. Gilbert,et al.  Design, synthesis, and evaluation of inhibitors of trypanosomal and leishmanial dihydrofolate reductase. , 1999, Journal of medicinal chemistry.

[42]  D. Andreu,et al.  The plasma membrane of Leishmania donovani promastigotes is the main target for CA(1-8)M(1-18), a synthetic cecropin A-melittin hybrid peptide. , 1998, The Biochemical journal.

[43]  P. A. Leonard,et al.  Triclosan: applications and safety. , 1996, American journal of infection control.

[44]  C. Corbett,et al.  A fast method for processing biologic material for electron microscopic diagnosis in infectious disease. , 1992, Ultrastructural pathology.

[45]  C. Hansch,et al.  Selective inhibition of Leishmania dihydrofolate reductase and Leishmania growth by 5-benzyl-2,4-diaminopyrimidines. , 1988, Molecular and biochemical parasitology.

[46]  M. Koyama,et al.  An improved colorimetric assay for interleukin 2. , 1986, Journal of immunological methods.

[47]  J El-On,et al.  Topical treatment of cutaneous leishmaniasis. , 1986, The Journal of investigative dermatology.

[48]  H. J. Cleave Acanthocephala from China. I. New Species and New Genera from Chinese Fishes , 1928, Parasitology.

[49]  H. Baylis Observations on certain Cestodes of Rats, with an Account of a New Species of Hymenolepis , 1922, Parasitology.