scholarly journals 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 anti-leishmanial compound

2021 ◽  
Author(s):  
Aya Hefnawy ◽  
Gabriel Negreira ◽  
Marlene Jara ◽  
James A. Cotton ◽  
Ilse Maes ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Visceral Leishmaniasis ◽  
Infectious Diseases ◽  
Leishmania Donovani ◽  
Neglected Tropical Diseases ◽  
Arms Race ◽  
Etiological Agent ◽  
Phenotypic Characterization ◽  
Tropical Diseases

AbstractThe implementation of prospective drug resistance (DR) studies in the R&D pipelines is a common practice for many infectious diseases, but not for Neglected Tropical Diseases. Here, we explored and demonstrated the importance of this approach, using as paradigms Leishmania donovani, the etiological agent of Visceral Leishmaniasis (VL), and TCMDC-143345, a promising compound of the GSK ‘Leishbox’ to treat VL. We experimentally selected resistance to TCMDC-143345 in vitro and characterized resistant parasites at genomic and phenotypic levels. We found that it took more time to develop resistance to TCMDC-143345 than to other drugs in clinical use and that there was no cross resistance to these drugs, suggesting a new and unique mechanism. By whole genome sequencing, we found two mutations in the gene encoding the L. donovani dynamin-1-like protein (LdoDLP1) that were fixed at highest drug pressure. Through phylogenetic analysis, we identified LdoDLP1 as a family member of the dynamin-related proteins, a group of proteins that impacts the shapes of biological membranes by mediating fusion and fission events, with a putative role in mitochondrial fission. We found that L. donovani lines genetically engineered to harbor the two identified LdoDLP1 mutations were resistant to TCMDC-143345 and displayed altered mitochondrial properties. By homology modeling, we showed how the two LdoDLP1 mutations may influence protein structure and function. Taken together, our data reveal a clear involvement of LdoDLP1 in the adaptation/resistance of L. donovani to TCMDC-143345.ImportanceHumans and their pathogens are continuously locked in a molecular arms race during which the eventual emergence of pathogen drug resistance (DR) seems inevitable. For neglected tropical diseases (NTDs), DR is generally studied retrospectively, once it has already been established in clinical settings. We previously recommended to keep one step ahead in the host-pathogen arms race and implement prospective DR studies in the R&D pipeline, a common practice for many infectious diseases, but not for NTDs. Here, using Leishmania donovani, the etiological agent of Visceral Leishmaniasis (VL), and TCMDC-143345, a promising compound of the GSK ‘Leishbox’ to treat VL, as paradigms, we experimentally selected resistance to the compound and proceeded to genomic and phenotypic characterization of DR parasites. The results gathered in the present study suggest a new DR mechanism involving the L. donovani dynamin-1 like protein (LdoDLP1) and demonstrate the practical relevance of prospective DR studies.

scholarly journals 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 ◽  
Author(s):  
Aya Hefnawy ◽  
Gabriel Negreira ◽  
Marlene Jara ◽  
James A. Cotton ◽  
Ilse Maes ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Leishmania Donovani ◽  
Neglected Tropical Diseases ◽  
Arms Race ◽  
Phenotypic Characterization ◽  
Clinical Settings ◽  
Tropical Diseases ◽  
Mechanism Of Resistance

Humans and their pathogens are continuously locked in a molecular arms race during which the eventual emergence of pathogen drug resistance (DR) seems inevitable. For neglected tropical diseases (NTDs), DR is generally studied retrospectively once it has already been established in clinical settings.

scholarly journals Efficacy and Safety of Paromomycin for Visceral Leishmaniasis: A Systematic Review

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Pashupati Pokharel ◽  
Rakesh Ghimire ◽  
Pratik Lamichhane
Keyword(s):  
Systematic Review ◽  
Drug Resistance ◽  
Visceral Leishmaniasis ◽  
South America ◽  
South Asia ◽  
Neglected Tropical Diseases ◽  
Tropical Diseases ◽  
Efficacy And Safety ◽  
Kala Azar ◽  
Resource Limited

Visceral leishmaniasis, also known as kala-azar is one of the most commonly neglected tropical diseases affecting a large number of rural and resource-limited people in South Asia, Africa, and South America. Paromomycin, an aminoglycoside drug, is frequently used for the treatment of visceral leishmaniasis. Despite limited therapies for visceral leishmaniasis and emerging drug resistance, a proper review on the action of paromomycin for kala-azar is lacking. This systematic review aims to look for the efficacy and safety aspects of paromomycin for the treatment of visceral leishmaniasis.

scholarly journals Meta-taxonomic Analysis of Prokaryotic and Eukaryotic Gut Flora in Stool Samples from Visceral Leishmaniasis Cases and Endemic Controls in Bihar State India

2019 ◽  
Author(s):  
Rachael Lappan ◽  
Cajsa Classon ◽  
Shashi Kumar ◽  
Om-Prakash Singh ◽  
Ricardo V. de Almeida ◽  
...  
Keyword(s):  
At Risk ◽  
Visceral Leishmaniasis ◽  
Immune Responses ◽  
Leishmania Donovani ◽  
Neglected Tropical Diseases ◽  
Rural India ◽  
Tropical Diseases ◽  
Host Immune Responses ◽  
Stool Samples ◽  
Bihar State

AbstractVisceral leishmaniasis (VL) caused by Leishmania donovani remains of public health concern in rural India. Those at risk of VL are also at risk of other neglected tropical diseases (NTDs) including soil transmitted helminths. Intestinal helminths are potent regulators of host immune responses sometimes mediated through cross-talk with gut microbiota. We evaluate a meta-taxonomic approach to determine the composition of prokaryotic and eukaryotic gut microflora using amplicon-based sequencing of 16S ribosomal RNA (16S rRNA) and 18S rRNA gene regions. The most abundant bacterial taxa identified in faecal samples from Bihar State India were Prevotella (37.1%), Faecalibacterium (11.3%), Escherichia-Shigella (9.1%), Alloprevotella (4.5%), Bacteroides (4.1%), Ruminococcaceae UCG-002 (1.6%), and Bifidobacterium (1.5%). Eukaryotic taxa identified (excluding plant genera) included Blastocystis (57.9%; Order: Stramenopiles), Dientamoeba (12.1%; Family: Tritrichomonadea), Pentatrichomonas (10.1%; Family: Trichomonodea), Entamoeba (3.5%; Family: Entamoebida), Ascaridida (0.8%; Family: Chromodorea; concordant with Ascaris by microscopy), Rhabditida (0.8%; Family: Chromodorea; concordant with Strongyloides), and Cyclophyllidea (0.2%; Order: Eucestoda; concordant with Hymenolepis). Overall alpha (Shannon’s, Faith’s and Pielou’s indices) and beta (Bray-Curtis dissimilarity statistic; weighted UniFrac distances) diversity of taxa did not differ significantly by age, sex, geographic subdistrict, or VL case (N=23) versus endemic control (EC; N=23) status. However, taxon-specific associations occurred: (i) Ruminococcaceae UCG-014 and Gastranaerophilales_uncultured bacterium were enriched in EC compared to VL cases; (ii) Pentatrichomonas was more abundant in VL cases than in EC, whereas the reverse occurred for Entamoeba. Across the cohort, high Escherichia-Shigella was associated with reduced bacterial diversity, while high Blastocystis was associated with high bacterial diversity and low Escherichia-Shigella. Individuals with high Blastocystis had low Bacteroidaceae and high Clostridiales vadin BB60 whereas the reverse held true for low Blastocystis. This scoping study provides useful baseline data upon which to develop a broader analysis of pathogenic enteric microflora and their influence on gut microbial health and NTDs generally.Author SummaryVisceral leishmaniasis (VL), also known as kala-azar, is a potentially fatal disease caused by intracellular parasites of the Leishmania donovani complex. VL is a serious public health problem in rural India, causing high morbidity and mortality, as well as major costs to local and national health budgets. People at risk of VL are also at risk of other neglected tropical diseases (NTDs) including soil transmitted helminths (worms). Intestinal worms are potent regulators of host immune responses often mediated through cross-talk with gut bacteria. Here we have used a modern DNA sequencing approach to determine the composition of microbiota in stool samples from VL cases and endemic controls. This allows us to determine all bacteria, as well as all single-celled and multicellular organisms, that comprise the microorganisms in the gut in a single sequencing experiment from a single stool sample. In addition to providing valuable information concerning commensal and pathogenic gut micro-organisms prevalent in this region of India, we find some specific associations between single-celled gut pathogens and VL case status.

scholarly journals Corrigendum: Genetic and Phenotypic Characterization of the Etiological Agent of Canine Orchiepididymitis Smooth Brucella sp. BCCN84.3

2019 ◽  
Vol 6 ◽  
Author(s):  
Caterina Guzmán-Verri ◽  
Marcela Suárez-Esquivel ◽  
Nazareth Ruíz-Villalobos ◽  
Michel S. Zygmunt ◽  
Mathieu Gonnet ◽  
...  
Keyword(s):  
Etiological Agent ◽  
Phenotypic Characterization

Chemotherapy of leishmaniasis: present challenges

Parasitology ◽  
2017 ◽  
Vol 145 (4) ◽  
pp. 464-480 ◽  
Author(s):  
SILVIA R. B. ULIANA ◽  
CRISTIANA T. TRINCONI ◽  
ADRIANO C. COELHO
Keyword(s):  
Drug Resistance ◽  
Drug Discovery ◽  
Side Effects ◽  
Visceral Leishmaniasis ◽  
Infectious Diseases ◽  
Treatment Failure ◽  
Chemotherapeutic Agents ◽  
Drug Combinations ◽  
New Drugs ◽  
Mechanisms Of Resistance

SUMMARYCutaneous and visceral leishmaniasis are amongst the most devastating infectious diseases of our time, affecting millions of people worldwide. The treatment of these serious diseases rely on a few chemotherapeutic agents, most of which are of parenteral use and induce severe side-effects. Furthermore, rates of treatment failure are high and have been linked to drug resistance in some areas. Here, we reviewed data on current chemotherapy practice in leishmaniasis. Drug resistance and mechanisms of resistance are described as well as the prospects for applying drug combinations for leishmaniasis chemotherapy. It is clear that efforts for discovering new drugs applicable to leishmaniasis chemotherapy are essential. The main aspects on the various steps of drug discovery in the field are discussed.

scholarly journals Neglected infectious diseases in the geriatrics

2021 ◽  
Author(s):  
Abrar Abdulfattah Al Yamani ◽  
Yahya Mohammad Falqi ◽  
Yussif Mohammed Alnawar ◽  
Lama Mohammed Almahrous ◽  
Haitham Ahmed Alwael ◽  
...  
Keyword(s):  
Infectious Diseases ◽  
Elderly Population ◽  
Neglected Tropical Diseases ◽  
Dengue Infection ◽  
The Elderly ◽  
Current Evidence ◽  
Severe Dengue ◽  
Tropical Diseases ◽  
Life Years ◽  
Populations At Risk

Infectious diseases in the elderly population pose a significant threat to their lives. Neglected tropical diseases significantly impact the health of the affected patients and populations at risk. Reports show that many of these disorders are among the highest ten most typical causes of disability-adjusted life years. In the present literature review, we have discussed the most common neglected tropical infections in geriatrics based on data from the current studies in the literature. Different infections can affect the geriatric population. However, evidence shows that this population is susceptible to developing severe disease-related conditions. This has been reported with dengue infection, onchocerciasis, and cholera. It has been demonstrated that ocular lesions and other clinical manifestations are highest among the elderly population with onchocerciasis. Severe dengue and dengue hemorrhagic fever are also reported at a high rate in this age group. Concurrent infections and disorders were documented with many of these infections, probably due to reduced immunity. Socioeconomic factors, co-morbidities, access to healthcare settings, environmental factors, sanitation, clustering, and overcrowding contribute to the frequency of neglected tropical diseases in the elderly. Further studies are still needed because the current report is scarce, which might underestimate the current evidence.

The Effect of Iodium 30c on Experimental Visceral Leishmaniasis

Homeopathy ◽  
2020 ◽  
Vol 109 (04) ◽  
pp. 213-223
Author(s):  
Jyoti Joshi ◽  
Chetna Bandral ◽  
Raj Kumar Manchanda ◽  
Anil Khurana ◽  
Debadatta Nayak ◽  
...  
Keyword(s):  
T Cells ◽  
Visceral Leishmaniasis ◽  
Amphotericin B ◽  
Cd8 T Cells ◽  
Therapeutic Efficacy ◽  
Leishmania Donovani ◽  
Neglected Tropical Diseases ◽  
Parasite Load ◽  
Poor People

Abstract Background Leishmaniasis is one of several neglected tropical diseases that warrant serious attention. A disease of socio-economically poor people, it demands safer and cheaper drugs that help to overcome the limitations faced by the existing anti-leishmanials. Complementary or traditional medicines might be a good option, with an added advantage that resistance may not develop against these drugs. Thus, the present investigation was performed to evaluate the anti-leishmanial efficacy of an ultra-diluted homeopathic medicine (Iodium 30c) in experimental visceral leishmaniasis (VL). Methods Compliant with strict ethical standards in animal experimentation, the study was performed in-vivo in inbred BALB/c mice which were injected intravenously with 1 × 107 promastigotes of Leishmania donovani before (therapeutic) or after (prophylactic) treatment with Iodium 30c for 30 days. In other groups of mice (n = 6 per group), amphotericin B served as positive control, infected animals as the disease control, while the naïve controls included normal animals; animals receiving only Iodium 30c or Alcohol 30c served as sham controls. The anti-leishmanial efficacy was assessed by determining the hepatic parasite load and analysing percentages of CD4+ and CD8+ T cells. Biochemical analysis and histological studies were performed to check any toxicities. Results Iodium-treated animals showed a significantly reduced parasite load (to 1503 ± 39 Leishman Donovan Units, LDU) as compared with the infected controls (4489 ± 256 LDU) (p < 0.05): thus, the mean therapeutic efficacy of Iodium 30c was 66.5%. In addition, the population of CD4+ and CD8+ T cells was significantly increased (p < 0.05) after treatment. No toxicity was observed, as evidenced from biochemical and histopathological studies of the liver and kidneys. Efficacy of Iodium 30c prophylaxis was 58.3%, while the therapeutic efficacy of amphotericin B was 85.9%. Conclusion This original study has shown that Iodium 30c had significant impact in controlling parasite replication in experimental VL, though the effect was less than that using standard pharmaceutical treatment.

scholarly journals Emerging Resistance of Neglected Tropical Diseases: A Scoping Review of the Literature

2019 ◽  
Vol 16 (11) ◽  
pp. 1925 ◽  
Author(s):  
Folahanmi T. Akinsolu ◽  
Priscilla O. Nemieboka ◽  
Diana W. Njuguna ◽  
Makafui N. Ahadji ◽  
Dora Dezso ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Assessment Tool ◽  
Neglected Tropical Diseases ◽  
Experimental Studies ◽  
Surveillance Systems ◽  
Tropical Diseases ◽  
Global Public Health ◽  
Preventive Chemotherapy ◽  
Clinical Resistance ◽  
Socio Demographic Factors

Background: Antimicrobial resistance (AMR) is a global public health threat with the potential to cause millions of deaths. There has been a tremendous increase in the use of antimicrobials, stemming from preventive chemotherapy elimination and control programs addressing neglected tropical diseases (NTDs). This study aims to identify the frequency of drug resistance for 11 major NTDs and 20 treatment drugs within a specific period by systematically analyzing the study design, socio-demographic factors, resistance, and countries of relevant studies. Methods: Adhering to PRISMA guidelines, we performed systematic reviews of the major 11 NTDs to identify publications on drug resistance between 2000 and 2016. A quality assessment tool adapted for evaluating observational and experimental studies was applied to assess the quality of eligible studies. Results: One of the major findings is that six NTDs have information on drug resistance, namely human African trypanosomiasis, leishmaniasis, onchocerciasis, schistosomiasis, soil-transmitted helminths, and trachoma. Many studies recorded resistance due to diagnostic tests, and few studies indicated clinical resistance. Although most studies were performed in Africa where there is the occurrence of several NTDs, there was no link between disease burden and locations of study. Conclusions: Based on this study we deduce that monitoring and surveillance systems need to be strengthened to enable the early detection of AMR and the mitigation of its global spread.

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