In-Depth Quantitative Proteomics Characterization of In Vitro Selected Miltefosine Resistance in Leishmania infantum
Abstract
:1. Introduction
2. Materials and Methods
2.1. Parasite Culture, Growth Curve and Susceptibility Test
2.2. Selection of Resistance
2.3. Sample Preparation and LC-MS/MS Analysis
2.4. Data Analysis
2.5. Enrichment Analysis Based on Gene Ontology and Metabolic Pathway Annotations
2.6. Statistical Analysis
3. Results and Discussion
3.1. In Vitro-Selected Miltefosine-Resistant L. infantum Line LiR Exhibits Reduced Drug Sensitivity and Has a Lower Rate of Growth Than the WT Strain
3.2. Miltefosine-Resistant Line and Wild-Type Strain Are Clearly Separated by Differences in Their Protein Abundances
3.3. The Overall Abundance of Mitochondrial Proteins, Flagellum/Cytoskeleton Proteins and Membrane Proteins Were Increased in Miltefosine-Resistant Parasites
3.4. There Are Significant Differences in Protein Abundance between the Wild-Type Strain and the Miltefosine-Resistant Line
3.5. Proteins Involved in Oxidative Phosphorylation Are Significantly Increased in Resistant Parasites
3.6. Miltefosine-Resistant Parasites Have a Lower Concentration of Proteins Canonically Involved in Oxidative Stress Response While Exhibiting Elevated Abundance of Sterol Biosynthesis Enzymes
3.7. Concentration Levels of ABC Transporters and a Phospholipid Transporting ATPase Involved in Miltefosine Resistance Are Significantly Different between WT and LiR Parasites
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Alvar, J.; Vélez, I.D.; Bern, C.; Herrero, M.; Desjeux, P.; Cano, J.; Jannin, J.; de Boer, M. Leishmaniasis worldwide and global estimates of its incidence. PLoS ONE 2012, 7, e35671. [Google Scholar]
- Ready, P. Epidemiology of visceral leishmaniasis. Clin. Epidemiol. 2014, 6, 147–154. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- World Health Organization (WHO). Global leishmaniasis surveillance, 2017−2018, and first report on five additional indicators. Wkly. Epidemiol. Rec. 2020, 25, 265–280. [Google Scholar]
- World Health Organization (WHO). Leishmaniasis. Available online: https://www.who.int/news-room/fact-sheets/detail/leishmaniasis (accessed on 1 February 2022).
- Pan American Health Organization. Leishmaniasis: Epidemiological Report of the Americas [Internet]; No. 10; PAHO: Washington, DC, USA, 2021; Available online: https://iris.paho.org/handle/10665.2/51742 (accessed on 1 February 2022).
- Murray, H.W.; Berman, J.D.; Davies, C.R.; Saravia, N.G. Advances in leishmaniasis. Lancet 2005, 366, 1561–1577. [Google Scholar] [CrossRef]
- Burza, S.; Croft, S.L.; Boelaert, M. Leishmaniasis. Lancet 2018, 392, 951–970. [Google Scholar] [CrossRef]
- Sundar, S.; More, D.K.; Singh, M.K.; Singh, V.P.; Sharma, S.; Makharia, A.; Kumar, P.C.; Murray, H.W. Failure of pentavalent antimony in visceral leishmaniasis in India: Report from the center of the Indian epidemic. Clin. Infect. Dis. 2000, 31, 1104–1107. [Google Scholar] [CrossRef] [Green Version]
- Alves, F.; Bilbe, G.; Blesson, S.; Goyal, V.; Monnerat, S.; Mowbray, C.; Muthoni Ouattara, G.; Pécoul, B.; Rijal, S.; Rode, J.; et al. Recent Development of Visceral Leishmaniasis Treatments: Successes, Pitfalls, and Perspectives. Clin. Microbiol. Rev. 2018, 31, e00048-18. [Google Scholar] [CrossRef] [Green Version]
- Sundar, S.; Jha, T.K.; Thakur, C.P.; Engel, J.; Sindermann, H.; Fischer, C.; Junge, K.; Bryceson, A.; Berman, J. Oral miltefosine for Indian visceral leishmaniasis. N. Engl. J. Med. 2002, 347, 1739–1746. [Google Scholar] [CrossRef] [Green Version]
- Food and Drug Administration (FDA). IMPAVIDO–Prescribing Information. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204684s000lbl.pdf (accessed on 1 February 2022).
- Ware, J.M.; O’Connell, E.M.; Brown, T.; Wetzler, L.; Talaat, K.R.; Nutman, T.B.; Nash, T.E. Efficacy and Tolerability of Miltefosine in the Treatment of Cutaneous Leishmaniasis. Clin. Infect. Dis. 2021, 73, e2457–e2562. [Google Scholar] [CrossRef]
- Soto, J.; Soto, P.; Ajata, A.; Rivero, D.; Luque, C.; Tintaya, C.; Berman, J. Miltefosine Combined with Intralesional Pentamidine for Leishmania braziliensis Cutaneous Leishmaniasis in Bolivia. Am. J. Trop. Med. Hyg. 2018, 99, 1153–1155. [Google Scholar] [CrossRef] [Green Version]
- Verma, N.K.; Dey, C.S. Possible mechanism of miltefosine-mediated death of Leishmania donovani. Antimicrob. Agents Chemother. 2004, 48, 3010–3015. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Paris, C.; Loiseau, P.M.; Bories, C.; Bréard, J. Miltefosine Induces Apoptosis-Like Death in Leishmania donovani Promastigotes. Antimicrob. Agents Chemother. 2004, 48, 852–859. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ministério da Agricultura, Pecuária e Abastecimento e Ministério da Saúde. Nota Técnica Conjunta No. 001/2016. Available online: https://www.sbmt.org.br/portal/wp-content/uploads/2016/09/nota-tecnica.pdf (accessed on 1 February 2022).
- Andrade, H.M.; Toledo, V.P.; Pinheiro, M.B.; Guimarães, T.M.; Oliveira, N.C.; Castro, J.A.; Silva, R.N.; Amorim, A.C.; Brandão, R.M.; Yoko, M.; et al. Evaluation of miltefosine for the treatment of dogs naturally infected with L. infantum (=L. chagasi) in Brazil. Vet. Parasitol. 2011, 181, 83–90. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chappuis, F.; Sundar, S.; Hailu, A.; Ghalib, H.; Rijal, S.; Peeling, R.W.; Alvar, J.; Boelaert, M. Visceral leishmaniasis: What are the needs for diagnosis, treatment and control? Nat. Rev. Microbiol. 2007, 5, 873–882. [Google Scholar] [CrossRef]
- Kumar, D.; Kulshrestha, A.; Singh, R.; Salotra, P. In vitro susceptibility of field isolates of Leishmania donovani to miltefosine and amphotericin B: Correlation with sodium antimony gluconate susceptibility and implications for treatment in areas of endemicity. Antimicrob. Agents. Chemother. 2009, 53, 835–838. [Google Scholar] [CrossRef] [Green Version]
- Dorlo, T.P.; Rijal, S.; Ostyn, B.; de Vries, P.J.; Singh, R.; Bhattarai, N.; Uranw, S.; Dujardin, J.C.; Boelaert, M.; Beijnen, J.H.; et al. Failure of miltefosine in visceral leishmaniasis is associated with low drug exposure. J. Infect. Dis. 2014, 210, 146–153. [Google Scholar] [CrossRef]
- Sundar, S.; Singh, A.; Rai, M.; Prajapati, V.K.; Singh, A.K.; Ostyn, B.; Boelaert, M.; Dujardin, J.C.; Chakravarty, J. Efficacy of miltefosine in the treatment of visceral leishmaniasis in India after a decade of use. Clin. Infect. Dis. 2012, 55, 543–550. [Google Scholar] [CrossRef] [Green Version]
- Rijal, S.; Ostyn, B.; Uranw, S.; Rai, K.; Bhattarai, N.R.; Dorlo, T.P.; Beijnen, J.H.; Vanaerschot, M.; Decuypere, S.; Dhakal, S.S.; et al. Increasing Failure of Miltefosine in the Treatment of Kala-azar in Nepal and the Potential Role of Parasite Drug Resistance, Reinfection, or Noncompliance. Clin. Infect. Dis. 2013, 56, 1530–1538. [Google Scholar] [CrossRef] [Green Version]
- Deep, D.K.; Singh, R.; Bhandari, V.; Verma, A.; Sharma, V.; Wajid, S.; Sundar, S.; Ramesh, V.; Dujardin, J.C.; Salotra, P. Increased miltefosine tolerance in clinical isolates of Leishmania donovani is associated with reduced drug accumulation, increased infectivity and resistance to oxidative stress. PLoS Negl. Trop. Dis. 2017, 11, e0005641. [Google Scholar] [CrossRef]
- Carnielli, J.B.; de Andrade, H.M.; Pires, S.F.; Chapeaurouge, A.D.; Perales, J.; Monti-Rocha, R.; Carvalho, S.F.; Ribeiro, L.P.; Dietze, R.; Figueiredo, S.G.; et al. Proteomic analysis of the soluble proteomes of miltefosine-sensitive and -resistant Leishmania infantum chagasi isolates obtained from Brazilian patients with different treatment outcomes. J. Proteom. 2014, 108, 198–208. [Google Scholar] [CrossRef] [Green Version]
- Carnielli, J.; Crouch, K.; Forrester, S.; Silva, V.C.; Carvalho, S.; Damasceno, J.D.; Brown, E.; Dickens, N.J.; Costa, D.L.; Costa, C.; et al. A Leishmania infantum genetic marker associated with miltefosine treatment failure for visceral leishmaniasis. eBioMedicine 2018, 36, 83–91. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Carnielli, J.; Monti-Rocha, R.; Costa, D.L.; Molina Sesana, A.; Pansini, L.; Segatto, M.; Mottram, J.C.; Costa, C.; Carvalho, S.; Dietze, R. Natural Resistance of Leishmania infantum to Miltefosine Contributes to the Low Efficacy in the Treatment of Visceral Leishmaniasis in Brazil. Am. J. Trop. Med. Hyg. 2019, 101, 789–794. [Google Scholar] [CrossRef] [PubMed]
- Schwabl, P.; Boité, M.C.; Bussotti, G.; Jacobs, A.; Andersson, B.; Moreira, O.; Freitas-Mesquita, A.L.; Meyer-Fernandes, J.R.; Telleria, E.L.; Traub-Csekö, Y.; et al. Colonization and genetic diversification processes of Leishmania infantum in the Americas. Commun. Biol. 2021, 4, 139. [Google Scholar] [CrossRef] [PubMed]
- Espada, C.R.; Levatti, E.; Boité, M.C.; Lamounier, D.; Alvar, J.; Cupolillo, E.; Costa, C.; Rode, J.; Uliana, S. In Vitro Susceptibility to Miltefosine of Leishmania infantum (syn. L. chagasi) Isolates from Different Geographical Areas in Brazil. Microorganisms 2021, 9, 1228. [Google Scholar] [CrossRef]
- Mondelaers, A.; Sanchez-Cañete, M.P.; Hendrickx, S.; Eberhardt, E.; Garcia-Hernandez, R.; Lachaud, L.; Cotton, J.; Sanders, M.; Cuypers, B.; Imamura, H.; et al. Genomic and Molecular Characterization of Miltefosine Resistance in Leishmania infantum Strains with Either Natural or Acquired Resistance through Experimental Selection of Intracellular Amastigotes. PLoS ONE 2016, 8, e0154101. [Google Scholar] [CrossRef]
- Bhandari, V.; Kulshrestha, A.; Deep, D.K.; Stark, O.; Prajapati, V.K.; Ramesh, V.; Sundar, S.; Schonian, G.; Dujardin, J.C.; Salotra, P. Drug susceptibility in Leishmania isolates following miltefosine treatment in cases of visceral leishmaniasis and post kala-azar dermal leishmaniasis. PLoS Negl. Trop. Dis. 2012, 6, e1657. [Google Scholar] [CrossRef]
- Hendrickx, S.; Beyers, J.; Mondelaers, A.; Eberhardt, E.; Lachaud, L.; Delputte, P.; Cos, P.; Maes, L. Evidence of a drug-specific impact of experimentally selected paromomycin and miltefosine resistance on parasite fitness in Leishmania infantum. J. Antimicrob. Chemother. 2016, 71, 1914–1921. [Google Scholar] [CrossRef] [Green Version]
- Eberhardt, E.; Bulté, D.; Van Bockstal, L.; Van den Kerkhof, M.; Cos, P.; Delputte, P.; Hendrickx, S.; Maes, L.; Caljon, G. Miltefosine enhances the fitness of a non-virulent drug-resistant Leishmania infantum strain. J. Antimicrob. Chemother. 2019, 74, 395–406. [Google Scholar] [CrossRef]
- Vergnes, B.; Gourbal, B.; Girard, I.; Sundar, S.; Drummelsmith, J.; Ouellette, M. A proteomics screen implicates HSP83 and a small kinetoplastid calpain-related protein in drug resistance in Leishmania donovani clinical field isolates by modulating drug-induced programmed cell death. Mol. Cell. Proteom. 2007, 6, 88–101. [Google Scholar] [CrossRef] [Green Version]
- El Fadili, K.; Drummelsmith, J.; Roy, G.; Jardim, A.; Ouellette, M.A. Down regulation of KMP-11 in Leishmania infantum axenic antimony resistant amastigotes as revealed by a proteomic screen. Exp. Parasitol. 2009, 123, 51–57. [Google Scholar] [CrossRef]
- Matrangolo, F.S.; Liarte, D.B.; Andrade, L.C.; de Melo, M.F.; Andrade, J.M.; Ferreira, R.F.; Santiago, A.S.; Pirovani, C.P.; Silva-Pereira, R.A.; Murta, S.M. Comparative proteomic analysis of antimony-resistant and -susceptible Leishmania braziliensis and Leishmania infantum chagasi lines. Mol. Biochem. Parasitol. 2013, 190, 63–75. [Google Scholar] [CrossRef] [PubMed]
- Vincent, I.M.; Racine, G.; Légaré, D.; Ouellette, M. Mitochondrial Proteomics of Antimony and Miltefosine Resistant Leishmania infantum. Proteomes 2015, 3, 328–346. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Moreira, D.; Pescher, P.; Laurent, C.; Lenormand, P.; Späth, G.F.; Murta, S.M. Phosphoproteomic analysis of wild-type and antimony-resistant Leishmania braziliensis lines by 2D-DIGE technology. Proteomics 2015, 15, 2999–3019. [Google Scholar] [CrossRef] [PubMed]
- Vacchina, P.; Norris-Mullins, B.; Carlson, E.S.; Morales, M.A. A mitochondrial HSP70 (HSPA9B) is linked to miltefosine resistance and stress response in Leishmania donovani. Parasit. Vectors 2016, 9, 621. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Saboia-Vahia, L.; de Jesus, J.B.; Cuervo, P. The Role of Proteomics in the Study of Drug Resistance. In Drug Resistance in Leishmania Parasites; Ponte-Sucre, A., Padrón-Nieves, M., Eds.; Springer Nature Switzerland AG: Cham, Switzerland, 2018; pp. 209–245. [Google Scholar] [CrossRef]
- Douanne, N.; Dong, G.; Douanne, M.; Olivier, M.; Fernandez-Prada, C. Unravelling the proteomic signature of extracellular vesicles released by drug-resistant Leishmania infantum parasites. PLoS Negl. Trop. Dis. 2020, 14, e0008439. [Google Scholar] [CrossRef] [PubMed]
- Liarte, D.B.; Murta, S.M. Selection and phenotype characterization of potassium antimony tartrate-resistant populations of four New World Leishmania species. Parasitol. Res. 2010, 107, 205–212. [Google Scholar] [CrossRef]
- Pinho, N.; Wiśniewski, J.R.; Dias-Lopes, G.; Saboia-Vahia, L.; Bombaça, A.C.S.; Mesquita-Rodrigues, C.; Menna-Barreto, R.; Cupolillo, E.; de Jesus, J.B.; Padrón, G.; et al. In-Depth quantitative proteomics uncovers specie-specific metabolic programs in Leishmania (Viannia) species. PLoS Negl. Trop. Dis. 2020, 14, e0008509. [Google Scholar] [CrossRef]
- Pinho, N.; Bombaça, A.; Wiśniewski, J.; Dias-Lopes, G.; Saboia-Vahia, L.; Cupolillo, E.; de Jesus, J.; de Almeida, R.; Padrón, G.; Menna-Barreto, R.; et al. Nitric Oxide Resistance in Leishmania (Viannia) braziliensis Involves Regulation of Glucose Consumption, Glutathione Metabolism and Abundance of Pentose Phosphate Pathway Enzymes. Antioxidants 2022, 11, 277. [Google Scholar] [CrossRef]
- Wiśniewski, J.R.; Zougman, A.; Nagaraj, N.; Mann, M. Universal sample preparation method for proteome analysis. Nat. Methods 2009, 6, 359–362. [Google Scholar] [CrossRef]
- Wiśniewski, J.R. Filter-Aided Sample Preparation: The versatile and efficient method for proteomic analysis. Methods Enzymol. 2017, 585, 15–27. [Google Scholar] [CrossRef]
- Wiśniewski, J.R. Label-Free and standard-free absolute quantitative proteomics using the “total protein” and “proteomic ruler” approaches. Methods Enzymol. 2017, 585, 49–60. [Google Scholar] [CrossRef] [PubMed]
- Tyanova, S.; Temu, T.; Sinitcyn, P.; Carlson, A.; Hein, M.Y.; Geiger, T.; Mann, M.; Cox, J. The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat. Methods 2016, 13, 731–740. [Google Scholar] [CrossRef] [PubMed]
- Perez-Riverol, Y.; Csordas, A.; Bai, J.; Bernal-Llinares, M.; Hewapathirana, S.; Kundu, D.J.; Inuganti, A.; Griss, J.; Mayer, G.; Eisenacher, M.; et al. The PRIDE database and related tools and resources in 2019: Improving support for quantification data. Nucleic Acids Res. 2019, 47, D442–D450. [Google Scholar] [CrossRef] [PubMed]
- Kanehisa, M.; Sato, Y. KEGG Mapper for inferring cellular functions from protein sequences. Protein Sci. 2020, 29, 28–35. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hefnawy, A.; Negreira, G.; Jara, M.; Cotton, J.A.; Maes, I.; D’Haenens, E.; Imamura, H.; Cuypers, B.; Monsieurs, P.; Mouchtoglou, C.; et al. Genomic and Phenotypic Characterization of Experimentally Selected Resistant Leishmania donovani Reveals a Role for Dynamin-1-Like Protein in the Mechanism of Resistance to a Novel Antileishmanial Compound. mBio 2022, 13, e0326421. [Google Scholar] [CrossRef] [PubMed]
- Bulté, D.; Van Bockstal, L.; Dirkx, L.; Van den Kerkhof, M.; De Trez, C.; Timmermans, J.P.; Hendrickx, S.; Maes, L.; Caljon, G. Miltefosine enhances infectivity of a miltefosine-resistant Leishmania infantum strain by attenuating its innate immune recognition. PLoS Negl. Trop. Dis. 2021, 15, e0009622. [Google Scholar] [CrossRef]
- Peacock, C.S.; Seeger, K.; Harris, D.; Murphy, L.; Ruiz, J.C.; Quail, M.A.; Peters, N.; Adlem, E.; Tivey, A.; Aslett, M.; et al. Comparative genomic analysis of three Leishmania species that cause diverse human disease. Nat. Genet. 2007, 39, 839–847. [Google Scholar] [CrossRef] [Green Version]
- González-de la Fuente, S.; Peiró-Pastor, R.; Rastrojo, A.; Moreno, J.; Carrasco-Ramiro, F.; Requena, J.M.; Aguado, B. Resequencing of the Leishmania infantum (strain JPCM5) genome and de novo assembly into 36 contigs. Sci. Rep. 2017, 7, 18050. [Google Scholar] [CrossRef]
- Aebischer, T. Leishmania spp. proteome data sets: A comprehensive resource for vaccine development to target visceral leishmaniasis. Front. Immunol. 2014, 5, 260. [Google Scholar] [CrossRef] [Green Version]
- Wiśniewski, J.R.; Vildhede, A.; Norén, A.; Artursson, P. In-depth quantitative analysis and comparison of the human hepatocyte and hepatoma cell line HepG2 proteomes. J. Proteom. 2016, 136, 234–247. [Google Scholar] [CrossRef]
- Franssen, S.U.; Durrant, C.; Stark, O.; Moser, B.; Downing, T.; Imamura, H.; Dujardin, J.C.; Sanders, M.J.; Mauricio, I.; Miles, M.A.; et al. Global genome diversity of the Leishmania donovani complex. eLife 2020, 9, e51243. [Google Scholar] [CrossRef] [PubMed]
- Imamura, H.; Downing, T.; Van den Broeck, F.; Sanders, M.J.; Rijal, S.; Sundar, S.; Mannaert, A.; Vanaerschot, M.; Berg, M.; De Muylder, G.; et al. Evolutionary genomics of epidemic visceral leishmaniasis in the Indian subcontinent. eLife 2016, 5, e12613. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dumetz, F.; Cuypers, B.; Imamura, H.; Zander, D.; D’Haenens, E.; Maes, I.; Domagalska, M.A.; Clos, J.; Dujardin, J.C.; De Muylder, G. Molecular Preadaptation to Antimony Resistance in Leishmania donovani on the Indian Subcontinent. mSphere 2018, 3, e00548-17. [Google Scholar] [CrossRef] [Green Version]
- Santa-Rita, R.M.; Henriques-Pons, A.; Barbosa, H.S.; de Castro, S.L. Effect of the lysophospholipid analogues edelfosine, ilmofosine and miltefosine against Leishmania amazonensis. J. Antimicrob. Chemother. 2004, 54, 704–710. [Google Scholar] [CrossRef] [PubMed]
- Luque-Ortega, J.R.; Rivas, L. Miltefosine (hexadecylphosphocholine) inhibits cytochrome c oxidase in Leishmania donovani promastigotes. Antimicrob. Agents Chemother. 2007, 51, 1327–1332. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Das, M.; Saudagar, P.; Sundar, S.; Dubey, V.K. Miltefosine-unresponsive Leishmania donovani has a greater ability than miltefosine-responsive L. donovani to resist reactive oxygen species. FEBS J. 2013, 280, 4807–4815. [Google Scholar] [CrossRef]
- Tomás, A.M.; Castro, H. Redox metabolism in mitochondria of trypanosomatids. Antioxid. Redox Signal. 2013, 19, 696–707. [Google Scholar] [CrossRef] [Green Version]
- Darling, T.N.; Blum, J.J. D-Lactate production by Leishmania braziliensis through the glyoxalase pathway. Mol. Biochem. Parasitol. 1988, 28, 121–127. [Google Scholar] [CrossRef]
- Wyllie, S.; Fairlamb, A.H. Methylglyoxal metabolism in trypanosomes and Leishmania. Semin. Cell Dev. Biol. 2011, 22, 271–277. [Google Scholar] [CrossRef] [Green Version]
- Rastrojo, A.; García-Hernández, R.; Vargas, P.; Camacho, E.; Corvo, L.; Imamura, H.; Dujardin, J.C.; Castanys, S.; Aguado, B.; Gamarro, F.; et al. Genomic and transcriptomic alterations in Leishmania donovani lines experimentally resistant to antileishmanial drugs. Int. J. Parasitol. Drugs Drug Resist. 2018, 8, 246–264. [Google Scholar] [CrossRef]
- Veronica, J.; Chandrasekaran, S.; Dayakar, A.; Devender, M.; Prajapati, V.K.; Sundar, S.; Maurya, R. Iron superoxide dismutase contributes to miltefosine resistance in Leishmania donovani. FEBS J. 2019, 286, 3488–3503. [Google Scholar] [CrossRef] [PubMed]
- Getachew, F.; Gedamu, L. Leishmania donovani mitochondrial iron superoxide dismutase A is released into the cytosol during miltefosine induced programmed cell death. Mol. Biochem. Parasitol. 2012, 183, 42–51. [Google Scholar] [CrossRef] [PubMed]
- Santi, A.; Silva, P.A.; Santos, I.; Murta, S. Downregulation of FeSOD-A expression in Leishmania infantum alters trivalent antimony and miltefosine susceptibility. Parasit. Vectors 2021, 14, 366. [Google Scholar] [CrossRef]
- Mukherjee, S.; Moitra, S.; Xu, W.; Hernandez, V.; Zhang, K. Sterol 14-α-demethylase is vital for mitochondrial functions and stress tolerance in Leishmania major. PLoS Pathog. 2020, 16, e1008810. [Google Scholar] [CrossRef] [PubMed]
- Mukherjee, S.; Xu, W.; Hsu, F.F.; Patel, J.; Huang, J.; Zhang, K. Sterol methyltransferase is required for optimal mitochondrial function and virulence in Leishmania major. Mol. Microbiol. 2019, 111, 65–81. [Google Scholar] [CrossRef] [Green Version]
- McCall, L.I.; El Aroussi, A.; Choi, J.Y.; Vieira, D.F.; De Muylder, G.; Johnston, J.B.; Chen, S.; Kellar, D.; Siqueira-Neto, J.L.; Roush, W.R.; et al. Targeting Ergosterol biosynthesis in Leishmania donovani: Essentiality of sterol 14 alpha-demethylase. PLoS Negl. Trop. Dis. 2015, 9, e0003588. [Google Scholar] [CrossRef] [Green Version]
- Higgins, C.F. ABC transporters: From microorganisms to man. Annu. Rev. Cell Biol. 1992, 8, 67–113. [Google Scholar] [CrossRef]
- Coelho, A.C.; Cotrim, P.C. The Role of ABC Transporters in Drug-Resistant Leishmania. In Drug Resistance in Leishmania Parasites; Ponte-Sucre, A., Padrón-Nieves, M., Eds.; Springer Nature Switzerland AG: Cham, Switzerland, 2018; pp. 247–272. [Google Scholar]
- Pérez-Victoria, J.M.; Pérez-Victoria, F.J.; Parodi-Talice, A.; Jiménez, I.A.; Ravelo, A.G.; Castanys, S.; Gamarro, F. Alkyl-lysophospholipid resistance in multidrug-resistant Leishmania tropica and chemosensitization by a novel P-glycoprotein-like transporter modulator. Antimicrob. Agents Chemother. 2001, 45, 2468–2474. [Google Scholar] [CrossRef] [Green Version]
- Castanys-Muñoz, E.; Alder-Baerens, N.; Pomorski, T.; Gamarro, F.; Castanys, S. A novel ATP-binding cassette transporter from Leishmania is involved in transport of phosphatidylcholine analogues and resistance to alkyl-phospholipids. Mol. Microbiol. 2007, 64, 1141–1153. [Google Scholar] [CrossRef]
- Pérez-Victoria, J.M.; Cortés-Selva, F.; Parodi-Talice, A.; Bavchvarov, B.I.; Pérez-Victoria, F.J.; Muñoz-Martínez, F.; Maitrejean, M.; Costi, M.P.; Barron, D.; Di Pietro, A.; et al. Combination of suboptimal doses of inhibitors targeting different domains of LtrMDR1 efficiently overcomes resistance of Leishmania spp. to Miltefosine by inhibiting drug efflux. Antimicrob. Agents Chemother. 2006, 50, 3102–3110. [Google Scholar] [CrossRef] [Green Version]
- Campos-Salinas, J.; León-Guerrero, D.; González-Rey, E.; Delgado, M.; Castanys, S.; Pérez-Victoria, J.M.; Gamarro, F. LABCG2, a new ABC transporter implicated in phosphatidylserine exposure, is involved in the infectivity and pathogenicity of Leishmania. PLoS Negl. Trop. Dis. 2013, 7, e2179. [Google Scholar] [CrossRef]
- Manzano, J.I.; Perea, A.; León-Guerrero, D.; Campos-Salinas, J.; Piacenza, L.; Castanys, S.; Gamarro, F. Leishmania LABCG1 and LABCG2 transporters are involved in virulence and oxidative stress: Functional linkage with autophagy. Parasit. Vectors 2017, 10, 267. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pérez-Victoria, F.J.; Gamarro, F.; Ouellette, M.; Castanys, S. Functional cloning of the miltefosine transporter. A novel P-type phospholipid translocase from Leishmania involved in drug resistance. J. Biol. Chem. 2003, 278, 49965–49971. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Saboia-Vahia, L.; Cuervo, P.; Wiśniewski, J.R.; Dias-Lopes, G.; Pinho, N.; Padrón, G.; de Pilla Varotti, F.; Murta, S.M.F. In-Depth Quantitative Proteomics Characterization of In Vitro Selected Miltefosine Resistance in Leishmania infantum. Proteomes 2022, 10, 10. https://doi.org/10.3390/proteomes10020010
Saboia-Vahia L, Cuervo P, Wiśniewski JR, Dias-Lopes G, Pinho N, Padrón G, de Pilla Varotti F, Murta SMF. In-Depth Quantitative Proteomics Characterization of In Vitro Selected Miltefosine Resistance in Leishmania infantum. Proteomes. 2022; 10(2):10. https://doi.org/10.3390/proteomes10020010
Chicago/Turabian StyleSaboia-Vahia, Leonardo, Patricia Cuervo, Jacek R. Wiśniewski, Geovane Dias-Lopes, Nathalia Pinho, Gabriel Padrón, Fernando de Pilla Varotti, and Silvane Maria Fonseca Murta. 2022. "In-Depth Quantitative Proteomics Characterization of In Vitro Selected Miltefosine Resistance in Leishmania infantum" Proteomes 10, no. 2: 10. https://doi.org/10.3390/proteomes10020010