scholarly journals Identification of P218 as a Potent Inhibitor of Mycobacteria Ulcerans DHFR

2020 ◽  
Author(s):  
Gustavo Pelicioli Riboldi ◽  
Rachael Zigweid ◽  
Peter J. Myler ◽  
Stephen J. Mayclin ◽  
Rafael Counago ◽  
...  
Keyword(s):  
Chronic Disease ◽  
Side Effects ◽  
Dihydrofolate Reductase ◽  
De Novo ◽  
Potent Inhibitor ◽  
Critical Role ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
De Novo Biosynthesis

<i>Mycobacterium ulcerans</i> is the causative agent of Buruli ulcer, a debilitating chronic disease that mainly affects the skin. Current treatments for Buruli ulcer are efficacious, but rely on the use of antibiotics with severe side effects. The enzyme dihydrofolate reductase (DHFR) plays a critical role in the de novo biosynthesis of folate species and is a validated target for several antimicrobials. Here we describe the biochemical and structural characterization of <i>M. ulcerans</i> DHFR and identified P218, a safe antifolate compound in clinical evaluation for malaria, as a potent inhibitor of this enzyme. We expect our results to advance <i>M. ulcerans</i> DHFR as a target for future structure-based drug discovery campaigns.

scholarly journals Identification of P218 as a Potent Inhibitor of Mycobacteria Ulcerans DHFR

2020 ◽  
Author(s):  
Gustavo Pelicioli Riboldi ◽  
Rachael Zigweid ◽  
Peter J. Myler ◽  
Stephen J. Mayclin ◽  
Rafael Counago ◽  
...  
Keyword(s):  
Chronic Disease ◽  
Side Effects ◽  
Dihydrofolate Reductase ◽  
De Novo ◽  
Potent Inhibitor ◽  
Critical Role ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
De Novo Biosynthesis

<i>Mycobacterium ulcerans</i> is the causative agent of Buruli ulcer, a debilitating chronic disease that mainly affects the skin. Current treatments for Buruli ulcer are efficacious, but rely on the use of antibiotics with severe side effects. The enzyme dihydrofolate reductase (DHFR) plays a critical role in the de novo biosynthesis of folate species and is a validated target for several antimicrobials. Here we describe the biochemical and structural characterization of <i>M. ulcerans</i> DHFR and identified P218, a safe antifolate compound in clinical evaluation for malaria, as a potent inhibitor of this enzyme. We expect our results to advance <i>M. ulcerans</i> DHFR as a target for future structure-based drug discovery campaigns.

scholarly journals Molecular and epidemiological characterization of recurrent Mycobacterium ulcerans infections in Benin

2021 ◽  
Vol 15 (12) ◽  
pp. e0010053
Author(s):  
Ronald Gnimavo ◽  
Alban Besnard ◽  
Horace Degnonvi ◽  
Juliana Pipoli Da Fonseca ◽  
Marie Kempf ◽  
...  
Keyword(s):  
Random Distribution ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Neglected Tropical Disease ◽  
Contaminated Water ◽  
Ulcer Recurrence ◽  
Paradoxical Reaction ◽  
Environmental Mycobacterium ◽  
Epidemiological Characterization

Background Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans, an environmental mycobacterium. Although transmission of M. ulcerans remains poorly understood, the main identified risk factor for acquiring Buruli ulcer is living in proximity of potentially contaminated water sources. Knowledge about the clinical features of Buruli ulcer and its physiopathology is increasing, but little is known about recurrence due to reinfection. Methodology/Principal findings We describe two patients with Buruli ulcer recurrence due to reinfection with M. ulcerans, as demonstrated by comparisons of DNA from the strains isolated at the time of the first diagnosis and at recurrence. Based on the spatial distribution of M. ulcerans genotypes in this region and a detailed study of the behavior of these two patients with respect to sources of water as well as water bodies and streams, we formulated hypotheses concerning the sites at which they may have been contaminated. Conclusions/Significance Second episodes of Buruli ulcer may occur through reinfection, relapse or a paradoxical reaction. We formally demonstrated that the recurrence in these two patients was due to reinfection. Based on the sites at which the patients reported engaging in activities relating to water, we were able to identify possible sites of contamination. Our findings indicate that the non-random distribution of M. ulcerans genotypes in this region may provide useful information about activities at risk.

scholarly journals Mucocutaneous side effects of brequinar sodium. A new inhibitor of pyrimidine de novo biosynthesis

Cancer ◽  
1989 ◽  
Vol 63 (2) ◽  
pp. 243-248 ◽  
Author(s):  
G. Schwartsmann ◽  
E. Bork ◽  
J. B. Vermorken ◽  
C. Nieboer ◽  
P. Dodion ◽  
...  
Keyword(s):  
Side Effects ◽  
De Novo ◽  
De Novo Biosynthesis ◽  
Brequinar Sodium

scholarly journals Molecular characterization of Mycobacterium ulcerans DNA gyrase and identification of mutations reduced susceptibility against quinolones in vitro

2021 ◽  
Author(s):  
Hyun Kim ◽  
Shigtarou Mori ◽  
Tsuyoshi Kenri ◽  
Yasuhiko Suzuki
Keyword(s):  
Buruli Ulcer ◽  
Dna Gyrase ◽  
Resistance Mechanisms ◽  
Docking Studies ◽  
Mycobacterium Ulcerans ◽  
Amino Acid Residues ◽  
Wild Type Enzyme ◽  
Ulcer Disease

ABSTRACTBuruli ulcer disease is a neglected necrotizing and disabling cutaneous tropical illness caused by Mycobacterium ulcerans (Mul). Fluoroquinolone (FQ), used in the treatment of this disease, has been known to act by inhibiting the enzymatic activities of DNA gyrase; however, the detailed molecular basis of these characteristics and the FQ resistance mechanisms in Mul remains unknown. This study investigated the detailed molecular mechanism of Mul DNA gyrase and the contribution of FQ resistance in vitro using recombinant proteins from the Mul subsp. shinshuense and Agy99 strains with reduced sensitivity to FQs. The IC50 of FQs against Ala91Vla and Asp95Gly mutants of Mul shinshuense and Agy99 GyrA subunits were 3.7- to 42.0-fold higher than those against wild-type enzyme. Similarly, the CC25 was 10- to 210-fold higher than those for the WT enzyme. Furthermore, the interaction between the amino acid residues of WT/mutant Mul DNA gyrase and FQ side chains was assessed via molecular docking studies. This is the first detailed study showing the contribution of Mul DNA GyrA subunit mutations to reduce the susceptibility against FQs.

scholarly journals Characterization of the Molecular Lipophilicity of Mycolactones A/B and C, Infectious Factors of Mycobacterium ulcerans Agent of Buruli Ulcer

2021 ◽  
pp. 18-27
Author(s):  
Kadjo François Kassi ◽  
Jean Missa Ehouman ◽  
Mamadou Guy-Richard Koné ◽  
Lamoussa Ouattara ◽  
Georges Stéphane Dembélé ◽  
...  
Keyword(s):  
Biological Activities ◽  
Subcutaneous Fat ◽  
Buruli Ulcer ◽  
Control Program ◽  
Mycobacterium Ulcerans ◽  
Key Factors ◽  
Infected Area ◽  
Very High

The work was undertaken as part of the Buruli ulcer control program. It is particularly about the determination of the lipophilicity of mycolactones A/B and C, infectious factors of Mycobacterium ulcerans, the agent of Buruli ulcer. The REKKER method and some free software such as MOLINSPIRATION, ACD/ChemSketch and EPIWED were used for the determination of the lipophilicity of mycolactones A/B and C. Very high logP values were found and respectively ranged from 12.11 to 11.41 for mycolactone A/B and 11.69 to 11.58 for mycolactone C. These values obtained from this coefficient, show that mycolactones A/B and C are naturally lipophilic and that actually reflects their effective presence in the subcutaneous fat of the infected area. These results are very encouraging and promising. They are key factors for a better understanding of the biological activities of the two mycolactones and pave the way for the proposal of a mechanism to annihilate their destructive effects.

scholarly journals Rigorous estimation of post-translational proteasomal splicing in the immunopeptidome

2021 ◽  
Author(s):  
Kamil J Cygan ◽  
Ehdieh Khaledian ◽  
Lili Blumenberg ◽  
Robert R Salzler ◽  
Darshit Shah ◽  
...  
Keyword(s):  
Immune Response ◽  
Autoimmune Disease ◽  
De Novo ◽  
Critical Role ◽  
Unknown Origin ◽  
Peptide Sequencing ◽  
De Novo Peptide Sequencing ◽  
De Novo Peptide

Recently, de novo peptide sequencing has made it possible to gain new insights into the human immunopeptidome without relying on peptide databases, while identifying peptides of unknown origin. Many recent studies have attributed post-translational proteasomal splicing as the origin of those peptides. Here, we describe a peptide source assignment workflow to rigorously assign the source of de novo sequenced peptides and find that the estimated extent of post-translational splicing in the immunopeptidome is much lower than previously reported. Our approach demonstrates that many peptides that were thought to be post-translationally spliced are likely linear peptides, and many peptides that were thought to be trans-spliced could be cis-spliced. We believe our approach furthers the understanding of post-translationally spliced peptides and thus improves the characterization of immunopeptidome which plays a critical role in the immune response to antigens in cancer, autoimmune disease, and infections.

Conventional Versus Natural Alternative Treatments for Leishmaniasis: A Review

2018 ◽  
Vol 18 (15) ◽  
pp. 1275-1286 ◽  
Author(s):  
Luiz Felipe Domingues Passero ◽  
Lucas Antal Cruz ◽  
Gabriela Santos-Gomes ◽  
Eliana Rodrigues ◽  
Márcia Dalastra Laurenti ◽  
...  
Keyword(s):  
Side Effects ◽  
Visceral Leishmaniasis ◽  
Traditional Knowledge ◽  
Conventional Therapy ◽  
Pathogenic Species ◽  
Action Mechanism ◽  
In Vivo Assays ◽  
Clinical Forms

Leishmaniasis is a neglected disease caused by protozoan belonging to the Leishmania genus. There are at least 16 pathogenic species for humans that are able to cause different clinical forms, such as cutaneous or visceral leishmaniasis. In spite of the different species and clinical forms, the treatment is performed with few drug options that, in most cases, are considered outdated. In addition, patients under classical treatment show serious side effects during drug administration, moreover parasites are able to become resistant to medicines. Thus, it is believed and well accepted that is urgent and necessary to develop new therapeutic options to overpass these concerns about conventional therapy of leishmaniasis. The present review will focus on the efficacy, side effects and action mechanism of classic drugs used in the treatment of leishmaniasis, as well as the importance of traditional knowledge for directing a rational search toward the discovery and characterization of new and effective molecules (in vivo assays) from plants to be used against leishmaniasis.

Interactions between ecological and socio-economic drivers of Buruli ulcer burden in Sub-Saharan Africa: opportunities for an improved control

2018 ◽  
Author(s):  
Andes Garchitorena ◽  
Matthew H. Bonds ◽  
Jean-Francois Guégan ◽  
Benjamin Roche
Keyword(s):  
Socioeconomic Factors ◽  
Disease Transmission ◽  
Access To Health Care ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Sub Saharan Africa ◽  
Aquatic Environments ◽  
Human Populations ◽  
Complex Interactions ◽  
Sub Saharan

This chapter provides an overview of the complex interactions between ecological and socioeconomic factors for the development and control of Buruli ulcer in Sub-Saharan Africa. We review key ecological and evolutionary processes driving the environmental persistence and proliferation of Mycobacterium ulcerans, the causative agent, within aquatic environments, as well as transmission processes from these aquatic environments to human populations. We also outline key socioeconomic factors driving the economic and health burden of Buruli ulcer in endemic regions, revealed by reciprocal feedbacks between poverty, disease transmission from exposure aquatic environments and disease progression to severe stages owing to low access to health care. The implications of such insights for disease control, both in terms of limitations of current strategies and directions for the future, are discussed.

Sign in / Sign up

Export Citation Format

Share Document