Drug resistance and treatment failure in leishmaniasis: A 21st century challenge

Ponte-Sucre, Alicia; Gamarro, Francisco; Dujardin, Jean‐Claude; Barrett, Michael P.; López‐Vélez, Rogelio; García-Hernández, Raquel; Pountain, Andrew W.; Mwenechanya, Roy; Papadopoulou, Barbara

doi:10.1371/journal.pntd.0006052

Cited by 684 publications

(538 citation statements)

References 135 publications

(167 reference statements)

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“…The digenetic life cycle of Leishmania parasites is characterized by the flagellated promastigotes found in the midgut of sandflies and the nonflagellated amastigotes in the phagolysosomes of mammalian macrophages. Current treatments are limited and drug resistance is a concern (Croft and Olliaro, ; Ponte‐Sucre et al , ). Without a safe vaccine, it is necessary to sustain a steady line of new drugs and drug targets.…”

Section: Introductionmentioning

confidence: 99%

Sterol methyltransferase is required for optimal mitochondrial function and virulence in Leishmania major

Mukherjee

Hsu

et al. 2018

Molecular Microbiology

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Summary Limited knowledge on the exact functions of ergostane-based sterols has hampered the application of sterol synthesis inhibitors against trypanosomatid parasites. Sterol methyltransferase (SMT) is directly involved in the synthesis of parasite specific C24-methylated sterols including ergosterol and 5-dehydroepisterol. While pharmacological studies hint at its potential as a drug target against trypanosomatids, direct evidence for the cellular function and essentiality of SMT is lacking. Here we characterized the SMT knockout mutants and their complemented strains in Leishmania major, the causative agent for cutaneous leishmaniasis. Deletion of SMT alleles led to a complete loss of C24-methylated sterols, which were replaced by cholestane-based sterols. SMT-null mutants were fully viable and replicative in culture but showed increased sensitivity to sphingolipid synthesis inhibition. They were not particularly vulnerable to heat, acidic pH, nitrosative or oxidative stress, yet exhibited high mitochondrial membrane potential and increased superoxide generation indicating altered physiology of the mitochondria. Despite possessing high levels of GPI-anchored glycoconjugates, SMT-null mutants showed significantly attenuated virulence in mice. In total, our study reveals that the biosynthesis of ergostane-based sterols is crucial for the proper function of mitochondria and the proliferation of Leishmania parasites in mammals.

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Section: Introductionmentioning

confidence: 99%

Sterol methyltransferase is required for optimal mitochondrial function and virulence in Leishmania major

Mukherjee

Hsu

et al. 2018

Molecular Microbiology

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“…Leishmaniasis remains one of the world's most neglected diseases in the 21st century . Cutaneous leishmaniasis (CL) is a parasitic infection induced by two species of Leishmania ( L .)…”

Section: Introductionmentioning

confidence: 99%

The outcome of arginase activity inhibition in BALB/c mice hosting Leishmania tropica

Nahidi

Gholami

Taslimi

et al. 2020

Parasite Immunology

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Two species of Leishmania (L), L. tropica and L. major, are among the main causative agents of cutaneous leishmaniasis. Arginase (ARG) is an essential enzyme for cell growth, thus an attractive drug target. In this study, we tried to survey the inhibitory impact of ARG by nor‐NOHA (N‐ω‐hydroxy‐L‐nor‐arginine) on in vivo infection caused by L. tropica. BALB/c mice were inoculated with L. tropicaEGFP‐LUC (Ltrop) or L. majorEGFP‐LUC (Lmj) and then were treated by nor‐NOHA. ARG inhibitor only indicated a delay in generation of a cutaneous lesion in inoculated footpad with nor‐NOHA‐Ltrop and nor‐NOHA‐Lmj. ARG activity has been significantly reduced in nor‐NOHA‐Ltrop group. In this group, ARG activity inhibition correlated with increased levels of nitric oxide (NO). In both inoculated mice with Ltrop or Lmj, parasite load showed a significant decrease at later steps during the CL course post‐treatment. In vivo bioluminescence intensity did not show any ARG's inhibitory effect on treated‐Ltrop. The findings verified that the ARG activity may partially control the L. tropica infection in BALB/c mice through reduction of parasite proliferation and parasite killing through NO generation. This effect is dose‐dependent.

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“…Current treatments are limited with toxic side effects and resistance is on the rise (3). Without a safe vaccine, it is necessary to identify new drug targets, develop new treatments, and decipher the mechanism of drug resistance in Leishmania (4).…”

Section: Introductionmentioning

confidence: 99%

Lathosterol oxidase (sterol C5-desaturase) deletion confers resistance to amphotericin B and sensitivity to acidic stress inLeishmania major

Frankfater²,

Hsu³

et al. 2020

Preprint

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8Lathosterol oxidase (LSO) catalyzes the formation of C5-C6 double bond in the synthesis 1 9 3 1 expression. Together, these findings suggest that the C5-C6 double bond is vital for the structure 3 2 of sterol core, and while the loss of LSO can lead to amphotericin B resistance, it also makes 3 3Leishmania parasites vulnerable to biologically relevant stress. 3 4 3 IMPORTANCE 3 5 Sterols are essential membrane components in eukaryotes and sterol synthesis inhibitors 3 6 can have potent effects against pathogenic fungi and trypanosomatids. Understanding the roles of 3 7 sterols will facilitate the development of new drugs and counter drug resistance. Lathosterol 3 8 oxidase (aka sterol C5-desaturase) is required for the formation of C5-C6 double bond in the 3 9 sterol core structure in mammals, fungi, protozoans, plants and algae. Functions of this C5-C6 4 0 double bond are not well understood. In this study, we generated and characterized a lathosterol 4 1 oxidase-null mutant in Leishmania major. Our data suggest that the C5-C6 double bond is vital 4 2 for the structure and membrane-stabilizing functions of leishmanial sterols. In addition, our 4 3 results imply that while mutations in lathosterol oxidase can confer resistance to amphotericin B, 4 4an important antifungal and antiprotozoal agent, the alteration in sterol structure leads to 4 5 significant defects in stress response that could be exploited for drug development. 4 6 4

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Drug resistance and treatment failure in leishmaniasis: A 21st century challenge

Cited by 684 publications

References 135 publications

Sterol methyltransferase is required for optimal mitochondrial function and virulence in Leishmania major

Sterol methyltransferase is required for optimal mitochondrial function and virulence in Leishmania major

The outcome of arginase activity inhibition in BALB/c mice hosting Leishmania tropica

Lathosterol oxidase (sterol C5-desaturase) deletion confers resistance to amphotericin B and sensitivity to acidic stress inLeishmania major

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