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 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 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 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.

scholarly journals Phenotypic characterization of drug resistance-associated mutations in HIV-1 RT connection and RNase H domains and their correlation with thymidine analogue mutations

2011 ◽  
Vol 66 (4) ◽  
pp. 702-708 ◽  
Author(s):  
R. B. Lengruber ◽  
K. A. Delviks-Frankenberry ◽  
G. N. Nikolenko ◽  
J. Baumann ◽  
A. F. Santos ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Rnase H ◽  
Phenotypic Characterization ◽  
Thymidine Analogue ◽  
Hiv 1

scholarly journals Phenotypic and genotypic characterization of multidrug-resistant Acinetobacter baumannii isolated in Algerian hospitals

2020 ◽  
Vol 14 (12) ◽  
pp. 1395-1401
Author(s):  
Nabila Benamrouche ◽  
Ourida Lafer ◽  
Lahcen Benmahdi ◽  
Akila Benslimani ◽  
Wahiba Amhis ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Intensive Care ◽  
Acinetobacter Baumannii ◽  
Multidrug Resistant ◽  
Phenotypic Characterization ◽  
Resistant Strains ◽  
Almost All ◽  
Encoding Genes ◽  
Phenotypic And Genotypic Characterization

Introduction: The aim of this study was to investigate the drug-resistance and the molecular characterization of carbapenemases, ESBL, and aminoglycoside-modifying enzymes among Acinetobacter baumannii clinical isolates in Algerian hospitals. Methodology: A total of 92 A. baumannii isolates were collected between 2012 and 2016. Antimicrobial susceptibility testings were performed for β-lactams, aminoglycosides, fluoroquinolones, trimethoprim-sulfamethoxazole, rifampicin and colistin. The phenotypic characterization of β-lactamases was investigated. For 30 randomly targeted strains, the carriage of the carbapenemases, ESBL and aminoglycoside-modifying enzymes -encoding genes was determined by PCR. Sequencing was carried out for carbapenemases and ESBL genes. Results: Most of the 92 isolates studied were recovered from hospitalized patients (93.5%) and were mainly from intensive care units (51.1%) and orthopedics (19.6%). The strains were collected primarily from low respiratory tract (33.7%), wounds (23.9%) and urine (16.3%). Multidrug-resistant A. baumannii strains were prevalent (96.7%). High rates of resistance were observed for almost all antibiotics tested (>70%) excluding rifampicin (7.6%) and colistin (5.4%). For the five colistin-resistant strains, MICs ranged between 4 and 128 µg/mL. Positive MBL (83.7%) and ESBL (23.9%) strains were identified. Regarding β-lactams, the blaNDM and both blaSHV and blaCTX-M1 genes were detected in five and two strains respectively. Sequencing of the genes revealed the presence of blaNDM-1, blaCTX-M-15, and blaSHV-33. For aminoglycosides, aac(6’)-Ib, ant(2’’)-I and aph(3’)-VI genes were detected in three, seven and six strains respectively. Conclusions: Here, we report the first co-occurrence of extended-spectrum β-lactamases SHV-33 and CTX-M-15, the carbapenemase NDM-1 and the emergence of colistin-resistant A. baumannii in Algerian hospitals.

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 Phenotypic characterization of human bone marrow granulocyte-macrophage forming progenitor cells

Blood ◽  
1981 ◽  
Vol 58 (5) ◽  
pp. 1047-1049
Author(s):  
MN Levine ◽  
JW Fay ◽  
NH Jones ◽  
RS Metzgar ◽  
BF Haynes
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Myeloid Cell ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Phenotypic Characterization ◽  
Clinical Settings ◽  
Cell Surface Antigens ◽  
Marrow Cells

Cell surface antigens of the human bone marrow CFU-C have been studied. Human marrow cells were incubated with a variety of monoclonal antisera and complement prior to culture in semisolid media. By using indirect immunofluorescent studies, the percentage of bone marrow cells binding the antibodies was determined. The CFU-C phenotype is HLA+, la+, 4F2+, 3A1-, and DUALL-1-. This study provides information that is useful in the study of myeloid cell ontogeny and necessary for the use of some of these reagents in the treatment of bone marrow cells prior to human bone marrow transplantation in various clinical settings.

scholarly journals Convergences between the Brazilian National Health Plan and scientific articles on Neglected Tropical Diseases

RECIIS ◽  
2021 ◽  
Vol 15 (2) ◽  
Author(s):  
Natanael Vitor Sobral ◽  
Viviane Martha Santos de Morais ◽  
Leilah Santiago Bufrem ◽  
Raimundo Nonato Macedo dos Santos ◽  
Fabio Mascarenhas e Silva
Keyword(s):  
Health Plan ◽  
National Health ◽  
Neglected Tropical Diseases ◽  
Health Planning ◽  
Tropical Diseases ◽  
Scientific Publications ◽  
National Health Plan ◽  
Institutional Researchers ◽  
Snake Bites

In Brazil, the National Health Plan (NHP) was the central instrument for public health planning from 2016 to 2019. In this paper, we show that there is a convergence between the Plan and the publication of scientific articles written by institutional researchers in the context of Neglected Tropical Diseases. The methodology used consisted of the following stages: identification of the universe of researchers, data collection, thematic characterization of Neglected Tropical Diseases in the Plan, organization of information, and production of indicators. In total, there were 2,719 researchers and 18,023 journal articles from 2015 to 2018. Of these, 2,541 articles, or 14.09%, were related to Neglected Tropical Diseases. Regarding the convergences, there was strong alignment with leishmaniasis, Chagas disease, dengue, leprosy, schistosomiasis, and Chikungunya fever. However, the coverage of topics by scientific publications was broader than that of the political instrument due to the inclusion of other themes: snake bites, helminthiasis and lymphatic filariasis.

scholarly journals Phenotypic Characterization of a Leishmania donovani Cyclophilin 40 Null Mutant

2016 ◽  
Vol 63 (6) ◽  
pp. 823-833 ◽  
Author(s):  
Wai-Lok Yau ◽  
Ulrike Lambertz ◽  
Lucie Colineau ◽  
Pascale Pescher ◽  
Andrea MacDonald ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Phenotypic Characterization ◽  
Null Mutant ◽  
Cyclophilin 40
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