Genomic Insight of Leishmania Parasite: In-Depth Review of Drug Resistance Mechanisms and Genetic Mutations

ACS Omega, Год журнала: 2024, Номер unknown

Опубликована: Март 8, 2024

Leishmaniasis, which is caused by a parasitic protozoan of the genus Leishmania, still major threat to global health, impacting millions individuals worldwide in endemic areas. Chemotherapy has been principal method for managing leishmaniasis; nevertheless, evolution drug resistance offers significant obstacle therapeutic success. Drug-resistant behavior these parasites complex phenomenon including both innate and acquired mechanisms. Resistance frequently related changes transportation, target alterations, enhanced efflux from pathogen. This review revealed specific genetic mutations Leishmania that are associated with commonly used antileishmanial drugs such as pentavalent antimonials, miltefosine, amphotericin B, paromomycin, resulting gene expression along functioning various proteins involved uptake, metabolism, efflux. Understanding linked essential creating approaches tackling avoiding spread drug-resistant variants. Based on treatments focus pathways could potentially improve treatment efficacy help long-term leishmaniasis control. More study needed uncover complete range generating medication develop new therapies based available information.

Язык: Английский

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Leishmania and HIV co-infection: first naturally Leishmania strain presenting decreased susceptibility to miltefosine, recovered from a patient in Portugal

Journal of Infection and Public Health, Год журнала: 2024, Номер 17(5), С. 810 - 818

Опубликована: Март 13, 2024

In Europe, up to 70% of visceral leishmaniasis (VL) cases occurring in adults living with HIV. People HIV VL co-infection often display persistent parasitemia, requiring chronic intermittent anti-Leishmania therapies. Consequently, frequent relapses and higher mortality rates are common these individuals. As such, it is paramount importance understand the reasons for parasite persistence improve infection management. To outline possible causes treatment failure context HIV-VL, we followed a person HIV-VL nine years 12-month period. We characterized: HIV-related clinicopathological alterations (CD4+ T counts viremia) Leishmania-specific seroreactivity, quantification pro-inflammatory cytokines upon stimulation studied Leishmania clinical isolate recovered during this The subject presented controlled viremia low CD4+ counts. remained PCR positive also seropositive. cellular response antigens was erratic. identified as first infantum case evidence decreased miltefosine susceptibility Portugal. Treatment multifactorial process driven by host determinants. Still, real-time determination drug profiles isolates an unexplored resource monitoring VL.

Язык: Английский

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Py-CoMFA, docking, and molecular dynamics simulations of Leishmania (L.) amazonensis arginase inhibitors

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Май 21, 2024

Abstract Leishmaniasis is a disease caused by protozoan of the genus Leishmania , affecting millions people, mainly in tropical countries, due to poor social conditions and low economic development. First-line chemotherapeutic agents involve highly toxic pentavalent antimonials, while treatment failure emergence drug-resistant strains. arginase (ARG) enzyme vital pathogenicity contributes higher infection rate, thus representing potential drug target. This study helps designing ARG inhibitors for leishmaniasis. Py-CoMFA (3D-QSAR) models were constructed using 34 from different chemical classes against L. (L.) amazonensis ( La ARG). The 3D-QSAR predictions showed an excellent correlation between experimental calculated pIC 50 values. molecular docking identified favorable hydrophobicity contribution phenyl cyclohexyl groups as substituents allosteric site. Molecular dynamics simulations selected protein–ligand complexes conducted understand derivatives’ interaction modes affinity both active sites. Two cinnamide compounds, 7g 7k identified, with similar structures reference 4h site inhibitor. These compounds can guide development more effective antileishmanial drugs.

Язык: Английский

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Repurposing approved protein kinase inhibitors as potent anti-leishmanials targeting Leishmania MAP kinases

Life Sciences, Год журнала: 2024, Номер 351, С. 122844 - 122844

Опубликована: Июнь 17, 2024

Язык: Английский

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Integrated subtractive genomics and structure-based approach to unravel the therapeutic drug target of Leishmania species

Archives of Microbiology, Год журнала: 2024, Номер 206(10)

Опубликована: Сен. 19, 2024

Язык: Английский

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Neglected Zoonotic Diseases: Advances in the Development of Cell-Penetrating and Antimicrobial Peptides against Leishmaniosis and Chagas Disease

Pathogens, Год журнала: 2023, Номер 12(7), С. 939 - 939

Опубликована: Июль 15, 2023

In 2020, the WHO established road map for neglected tropical diseases 2021–2030, which aims to control and eradicate 20 diseases, including leishmaniosis Chagas disease. addition, since 2015, has been developing a Global Action Plan on Antimicrobial Resistance. this context, achievement of innovative strategies as an alternative replace conventional therapies is first-order socio-sanitary priority, especially regarding endemic zoonoses in poor regions, such those caused by Trypanosoma cruzi Leishmania spp. infections. scenario, it worth highlighting group natural peptide molecules (AMPs CPPs) that are promising improving therapeutic efficacy against these zoonoses, they avoid development toxicity resistance treatments. This review presents novelties their ability cross whole system cell membranes well stimulate host immune defenses or even serve vectors molecules. The efforts biotechnological sector will make possible overcome limitations antimicrobial peptides through encapsulation functionalization methods obtain approval treatments be used clinical programs eradication

Язык: Английский

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Antileishmanial activity of Hesperetin on Leishmania donovani, in vitro and in silico inhibition of acetylcholinesterase and investigation of the targets sterol C-24 reductase and N-myristoyltransferase

Experimental Parasitology, Год журнала: 2025, Номер unknown, С. 108903 - 108903

Опубликована: Янв. 1, 2025

Язык: Английский

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Editorial: Latest findings on Leishmania parasites for better vaccine design and drug development

Frontiers in Microbiology, Год журнала: 2025, Номер 16

Опубликована: Янв. 30, 2025

Leishmania is a well-known unicellular parasite as the causative agent of debilitating vectorborne disease with diverse manifestations from fatal visceral (VL) and mucocutaneous (MCL) forms to self-healing cutaneous (CL). There an urgent need for protective vaccines also drug candidates due changes in map endemicity world-wide spread [1]. However, failure deep understanding real parasite-host-vector interaction has hampered development or effective treatments. Seyed et al. have discussed some underlying reasons vaccination correlates protection already identified mouse models vaccine formulations that better meet these criteria namely Live attenuated non-pathogenic species DNA vaccines. The application new technologies such CRISPR-Cas9 [2] generation antibiotic-free plasmids [3] are now available contribute solving inbuilt drawbacks associated platforms. Basically, against other relevant macrophage-resident parasites Trypanosoma cruzi benefit "concomitant immunity" which means "persistent, low-level infection" [4][5][6]. Cai demonstrated effectiveness experimental live chagas formulated on recombinant avirulent major (dhfr-ts -) expresses antigen. outcome study warrants further investigation live-attenuated both leishmaniasis chagas, two globally important infections.For moment, while human lag behind, chemotherapy still plays most role control. rising resistance current therapeutics, urges chemicals be replaced. Despite significant breakthroughs high throughput discovery, there identification promising novel anti-leishmania compounds. Almeida Machado advantaged repurposing involves identifying therapeutic uses existing drugs approved indications [7]. This group presented first time vitro subtilisin inhibitor (PF-429242), anti-viral drug, infantum parasite. PF-429242 suppresses protease induces several cellular alterations mitochondrial damage, oxidative stress autophagy addition modulating host immune response. Recently, synthetic biology come into focus enhance leishmaniasis, diagnostic tools therapeutics including immunetherapeutics. Synthetic multidisciplinary field science focuses living systems organisms, it applies engineering principles develop biological parts, devices, redesign found nature [8]. Khandibharad Singh, explain applications combat resulted pre-clinical achievements like circuits synthekines. Besides intensive Bamorovat introduced risk factors predispose meglumine antimoniate unresponsiveness tropica derived CL. Accordingly, treatment not only dependent genes [9] but demographical, clinical environmental factors, response, adherence by patients, genetic background even RNA virus infection parasites. Therefore, any (existing upcoming), regular monitoring prevent crucial [10].The last least critical play evaluating efficacies newly designed developed For species, preclinical model characteristics missing, example no reported standardized specific [11]. Species Viannia subgenus poorly infective mice generally asymptomatic induce mild resolves within few weeks almost elimination parasite, condition weakly resembles [12]. Munoz-Durango explained CL adapted panamensis isolate reproducibly dermal very similar BALB/c mice. They confirmed this suits pharmacological interventions regarding panamensis.To conclude, our antileishmanial complete. necessitates full emerging therapies maintain competence endemic areas. Second, we must rush substitute unaffordable high-risk use especially Advanced single-cell analysis controlled (CHIM) will hopefully make dream true near future.

Язык: Английский

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Evaluation of the Anti-Leishmanial Activity of the Hydroalcoholic Extract of Green Algae (Spirogyra): Investigation of Weight Indicators (Lesion Size and Organ Weights) in BALB/c Mice

Acta Parasitologica, Год журнала: 2025, Номер 70(1)

Опубликована: Фев. 1, 2025

Язык: Английский

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Synthesis and in vitro antitrypanosomatid activity of novel 5-nitroindole-rhodanine conjugates

Future Medicinal Chemistry, Год журнала: 2025, Номер unknown, С. 1 - 17

Опубликована: Фев. 24, 2025

Aim Trypanosomatid diseases, leishmaniasis and trypanosomiasis are vector-borne parasitic diseases that can cause death catastrophic economic losses for millions of people. The growing resistance trypanosomatid parasites to current treatments highlights the urgent need new therapeutic agents. This study explored 5-nitroindole-rhodanine conjugates identify promising compounds with potential future development as antitrypanosomatid treatments.

Язык: Английский

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