Molecular Mechanisms of Drug Resistance in Leishmania spp.
Abstract
1. Introduction
2. Available Treatments against Leishmaniasis
3. Genomic Changes and Drug Resistance
4. Changes in Transcriptomes Associated with Drug Resistance
5. Translational Control as a Major Driver of Drug Resistance
6. Changes in Metabolomes and Lipidomes Associated with Drug Resistance
7. Conclusions and Perspectives
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
Abbreviations
aa-tRNA | Aminoacyl transfer ribonucleic acid |
ABC | ATP binding cassette |
AmB | Amphotericin B |
APX | Ascorbate Peroxidase |
AQP1 | Aquaglyceroporin 1 |
ATP | Adenosine triphosphate |
BCAT | Branched-chain amino acids |
CDP | Cytidine-5’-diphosphate |
CNV | Copy number variation |
CTP | Cytidine-5’-triphosphate |
CDPK1 | Calcium dependent protein kinase 1 |
CL | Cutaneous Leishmaniasis |
CRISPR-Cas9 | Clustered Regularly Interspaced Short Palindromic Repeats-Protein 9 |
CYP51 | Sterol 14-demethylase |
D-LDH | D-lactate dehydrogenase-like protein |
DNA | Deoxyribonucleic Acid |
DEGs | Differentially expressed genes |
FDA | Food and Drug administration |
G6PDH | Glucose-6-Phosphate Dehydrogenase |
HAPT1 | High affinity pentamidine transporter |
HIV | Human immunodeficiency virus |
JAK-STAT | Janus kinase/signal transducers and activators of transcription |
LMT | Miltefosine Transporter gene |
MCL | Muco-Cutaneous Leishmaniasis |
MDR1 | Multi-drug resistance 1 |
MLT | Miltefosine |
mRNA | Messenger ribonucleic acid |
MRPA | Multidrug-resistance protein A |
NADPH | Nicotinamide adenine dinucleotide phosphate |
NTD | Neglected tropical disease |
PC | Phosphatidylcholines |
PE | Phosphatidylethanolamines |
PL | Phospholipids |
PMM | Paromomycin |
PRP1 | Pentamidine resistance protein 1 |
PTM | Pentamidine |
PTUs | Polycistronic transcription units |
PDR-1 | Pectin degradation regulator-1 |
RBP | RNA Binding protein |
RBPs | RNA-binding proteins |
RNAP II | RNA polymerase II |
RPP | Ribosomal protection protein |
rRNA | Ribosomal ribonucleic acid |
SbV | Pentavalent antimony |
SC5D | Sterol C5 -desaturase |
SMT | 24-sterol methyltransferase |
SNPs | Single nucleotide polymorphisms |
VL | Visceral Leishmaniasis |
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Current Drugs for Leishmaniasis Treatment | Mode of Action and Parasite Targeting | References |
---|---|---|
Pentavalent Antimony (SbV) | Inhibits the mitochondrial enzyme trypanothione reductase, increasing the parasite’s susceptibility to oxidative stress generated by the macrophage during infection. It can obstruct major energy-driven pathways such as fatty acid oxidation and glycolysis. | [35,48,49] |
Miltefosine (MLT) | Inhibits the enzyme cytochrome c oxidase located in the mitochondria, directly affecting energy production in the parasite. Also inhibits phosphatidylcholine synthesis, which affects lipid metabolism through the CDP-choline pathway by acting on CTP-phosphocholine cytidylyltransferase activity. | [50,51] |
Liposomal amphotericin B (AmB) | Forms transmembrane channels through the cell wall and is known to have a high affinity for ergosterol, causing micropores in the membrane, increasing permeability and ion loss, and resulting in cell death. | [52,53] |
Paromomycin (PMM) | Inhibits the cytosolic ribosome, affecting protein synthesis through binding to the 16S ribosomal unit and creating an alteration in its structure. | [54,55,56] |
Pentamidine (PTM) | Inhibits DNA and protein synthesis and causes cell-cycle arrest in the G2/M phase. Inhibits RNA polymerase, leading to apoptosis. Inhibits arginine transport. | [57,58] |
Drug | Gene Name | Genomic Changes | Effect Associated with Drug Resistance | Reference |
---|---|---|---|---|
Antimony | MRPA | Amplification | Increases drug efflux | [80,92] |
APX | Amplification | Protection from ROS accumulation | [84] | |
G6PDH | Amplification | Protection from ROS accumulation | [84,93] | |
AQP1 | Amplification, Deletion | Reduces drug uptake | [83] | |
MDR1 | Point mutation | Increases drug efflux | [86] | |
AmB | SMT | Deletion | Reduces drug uptake | [87] |
SC5D | Point mutation | Alters sterol biosynthesis | [94] | |
CYP51 | Point mutation | Alters sterol biosynthesis | [88] | |
LMT | Deletion, Point mutation | Alters sterol biosynthesis | [67] | |
Miltefosine | LMT | Deletion | Reduces drug uptake | [89] |
Paromomycin | Gene 18S RNA | Point mutation | Decreases binding of PMM | [81] |
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Moncada-Diaz, M.J.; Rodríguez-Almonacid, C.C.; Quiceno-Giraldo, E.; Khuong, F.T.H.; Muskus, C.; Karamysheva, Z.N. Molecular Mechanisms of Drug Resistance in Leishmania spp. Pathogens 2024, 13, 835. https://doi.org/10.3390/pathogens13100835
Moncada-Diaz MJ, Rodríguez-Almonacid CC, Quiceno-Giraldo E, Khuong FTH, Muskus C, Karamysheva ZN. Molecular Mechanisms of Drug Resistance in Leishmania spp. Pathogens. 2024; 13(10):835. https://doi.org/10.3390/pathogens13100835
Chicago/Turabian StyleMoncada-Diaz, Maria Juliana, Cristian Camilo Rodríguez-Almonacid, Eyson Quiceno-Giraldo, Francis T. H. Khuong, Carlos Muskus, and Zemfira N. Karamysheva. 2024. "Molecular Mechanisms of Drug Resistance in Leishmania spp." Pathogens 13, no. 10: 835. https://doi.org/10.3390/pathogens13100835
APA StyleMoncada-Diaz, M. J., Rodríguez-Almonacid, C. C., Quiceno-Giraldo, E., Khuong, F. T. H., Muskus, C., & Karamysheva, Z. N. (2024). Molecular Mechanisms of Drug Resistance in Leishmania spp. Pathogens, 13(10), 835. https://doi.org/10.3390/pathogens13100835