scholarly journals Exploiting reductive evolution in Mycobacterium ulcerans to develop a single-dose cure for Buruli ulcer

2021 ◽  
Author(s):  
◽  
Susan Thomas Sangeeta
Keyword(s):  
Single Dose ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Reductive Evolution

scholarly journals Buruli ulcer: reductive evolution enhances pathogenicity of Mycobacterium ulcerans

2009 ◽  
Vol 7 (1) ◽  
pp. 50-60 ◽  
Author(s):  
Caroline Demangel ◽  
Timothy P. Stinear ◽  
Stewart T. Cole
Keyword(s):  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Reductive Evolution

Impact of dose, duration and immune status on efficacy of ultrashort telacebec regimens in mouse models of Buruli ulcer

2021 ◽  
Author(s):  
Oliver Komm ◽  
Deepak V. Almeida ◽  
Paul J. Converse ◽  
Till F. Omansen ◽  
Eric L. Nuermberger
Keyword(s):  
Single Dose ◽  
Mouse Models ◽  
Immune Status ◽  
Buruli Ulcer ◽  
Dose Schedule ◽  
Mycobacterium Ulcerans ◽  
Resistant Bacteria ◽  
Treatment Regimens ◽  
Immunocompromised Hosts ◽  
Culture Negative

Telacebec (Q203) is a new anti-tuberculosis drug in clinical development with extremely potent activity against Mycobacterium ulcerans , the causative agent of Buruli ulcer (BU). The potency of Q203 has prompted investigation of its potential role in ultra-short, even single-dose, treatment regimens for BU in mouse models. However, the relationships of Q203 dose, dose schedule, duration and host immune status to treatment outcomes remain unclear, as does the risk of emergence of drug resistance with Q203 monotherapy. In the present study, we used mouse footpad infection models in immunocompetent BALB/c and immunocompromised SCID-beige mice to compare different Q203 doses, dosing schedules and treatment durations ranging from 1 day to 2 weeks, on long-term outcomes. We also tested whether combining Q203 with a second drug can increase efficacy. Overall, efficacy depended on total dose more than duration. Total doses of 5-20 mg/kg rendered nearly all BALB/c mice culture-negative 13-15 weeks post-treatment without selection of Q203-resistant bacteria. Addition of a second drug did not significantly increase efficacy. Although less potent in SCID-beige mice, Q203 still rendered the majority of footpads culture-negative at total doses of 10-20 mg/kg. Q203 resistance was identified in relapse isolates from some SCID-beige mice receiving monotherapy but not those receiving Q203 combined with bedaquiline or clofazimine. Overall, these results support the potential of Q203 monotherapy for single-dose or other ultra-short therapy for BU, although highly immunocompromised hosts may require higher doses or durations and/or combination therapy.

scholarly journals Reductive evolution and niche adaptation inferred from the genome of Mycobacterium ulcerans, the causative agent of Buruli ulcer

2007 ◽  
Vol 17 (2) ◽  
pp. 192-200 ◽  
Author(s):  
T. P. Stinear ◽  
T. Seemann ◽  
S. Pidot ◽  
W. Frigui ◽  
G. Reysset ◽  
...  
Keyword(s):  
Causative Agent ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Reductive Evolution ◽  
Niche Adaptation

scholarly journals Impact of dose, duration and host immune status on ultrashort telacebec treatment in a mouse model of Buruli ulcer

2021 ◽  
Author(s):  
Paul J Converse ◽  
Deepak Almeida ◽  
Oliver Komm ◽  
Eric Nuermberger
Keyword(s):  
Single Dose ◽  
Immune Status ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Mouse Strains ◽  
Resistant Bacteria ◽  
Treatment Regimens ◽  
End Of Treatment ◽  
Immunocompromised Hosts ◽  
Culture Negative

Telacebec (Q203) is a new anti-tuberculosis drug in clinical development with extremely potent activity againstMycobacterium ulcerans, the causative agent of Buruli ulcer (BU). The potency of Q203 has prompted investigation of its potential role in ultra-short, even single-dose, treatment regimens for BU in mouse models. However, the relationships of Q203 dose and duration and host immune status to treatment outcomes remain unclear, as does the risk of emergence of drug resistance with Q203 monotherapy. In the present study, immunocompetent BALB/c and immunocompromised SCID-beige mice were infected in both hind footpads and treated eight weeks later. In both mouse strains, controls received rifampin-clarithromycin; others received Q203 at 0.5 or 2 mg/kg/d for 5 or 10 days. Additionally, BALB/c mice received a single dose of 2.5 or 10 mg/kg or 3.3 mg/kg/d for 3 days. Treatment response was based on changes in footpad swelling and CFU counts at the end of treatment as well as 4 and 13 weeks after stopping treatment. Efficacy depended on total dose more than duration. Total doses of 5-20 mg/kg rendered nearly all BALB/c mice culture-negative 13 weeks post-treatment without selection of Q203-resistant bacteria. Although less potent in SCID-beige mice, Q203 still rendered the majority of footpads culture-negative at total doses of 10-20 mg/kg. However, Q203 resistance was identified in relapse isolates from some SCID-beige mice. Overall, these results support the potential of Q203 monotherapy for single-dose or other ultra-short therapy for BU, although highly immunocompromised hosts may require higher doses or durations and/or combination therapy.

scholarly journals Toward a Single-Dose Cure for Buruli Ulcer

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Sangeeta S. Thomas ◽  
Nitin Pal Kalia ◽  
Marie-Thérèse Ruf ◽  
Gerd Pluschke ◽  
Kevin Pethe
Keyword(s):  
Single Dose ◽  
Mouse Model ◽  
Clinical Management ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Clinical Use ◽  
Phase 2 ◽  
Mycobacterial Disease ◽  
Content Type ◽  
Clinical Candidate

ABSTRACT A single dose of Q203 (Telacebec), a phase 2 clinical candidate for tuberculosis, eradicates Mycobacterium ulcerans in a mouse model of Buruli ulcer infection without relapse up to 19 weeks posttreatment. Clinical use of Q203 may dramatically simplify the clinical management of Buruli ulcer, a neglected mycobacterial disease.

scholarly journals Toward a single dose cure for Buruli ulcer

2020 ◽  
Author(s):  
Sangeeta S Thomas ◽  
Nitin Pal Kalia ◽  
Marie-Thérèse Ruf ◽  
Gerd Pluschke ◽  
Kevin Pethe
Keyword(s):  
Single Dose ◽  
Mouse Model ◽  
Clinical Management ◽  
Buruli Ulcer ◽  
Post Treatment ◽  
Mycobacterium Ulcerans ◽  
Clinical Use ◽  
Phase 2 ◽  
Mycobacterial Disease ◽  
Clinical Candidate

AbstractA single dose of TELACEBEC (Q203), a phase 2 clinical candidate for tuberculosis, eradicates Mycobacterium ulcerans in a mouse model of Buruli ulcer infection without relapse up to 19 weeks post treatment. Clinical use of Q203 could dramatically simplify the clinical management of Buruli ulcer, a neglected mycobacterial disease.

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.

scholarly journals Cellular Immunity Confers Transient Protection in Experimental Buruli Ulcer following BCG or Mycolactone-Negative Mycobacterium ulcerans Vaccination

PLoS ONE ◽  
2012 ◽  
Vol 7 (3) ◽  
pp. e33406 ◽  
Author(s):  
Alexandra G. Fraga ◽  
Teresa G. Martins ◽  
Egídio Torrado ◽  
Kris Huygen ◽  
Françoise Portaels ◽  
...  
Keyword(s):  
Cellular Immunity ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans

scholarly journals Community-based geographical distribution of Mycobacterium ulcerans VNTR-genotypes from the environment and humans in the Nyong valley, Cameroon

2021 ◽  
Vol 49 (1) ◽  
Author(s):  
Francis Zeukeng ◽  
Anthony Ablordey ◽  
Solange E. Kakou-Ngazoa ◽  
Stephen Mbigha Ghogomu ◽  
David N’golo Coulibaly ◽  
...  
Keyword(s):  
Environmental Samples ◽  
Tandem Repeats ◽  
Buruli Ulcer ◽  
Variable Number ◽  
Mycobacterium Ulcerans ◽  
Community Based ◽  
Human Samples ◽  
Route Of Transmission ◽  
Mode Of Transmission ◽  
Animal Reservoirs

Abstract Background Genotyping is a powerful tool for investigating outbreaks of infectious diseases and it can provide useful information such as identifying the source and route of transmission, and circulating strains involved in the outbreak. Genotyping techniques based on variable number of tandem repeats (VNTR) are instrumental in detecting heterogeneity in Mycobacterium ulcerans (MU) and also for discriminating MU from other mycobacteria species. Here, we describe and map the distribution of MU genotypes in Buruli ulcer (BU) endemic communities of the Nyong valley in Cameroon. We also tested the hypothesis of whether the suspected animal reservoirs of BU that share the human microhabitat are shedding contaminated fecal matters and saliva into their surrounding environments. Methods Environmental samples from suspected MU-risk factors and lesion swabs from human patients were sampled in BU-endemic communities and tested for the presence of MU by qPCR targeting three independent sequences (IS2404, IS2606, KR-B). Positive samples to MU were further genotyped by VNTR with confirmation by sequencing of four loci (MIRU1, Locus 6, ST1, Locus 19). Results MU was detected in environmental samples including water bodies (23%), biofilms (14%), detritus (10%), and in human patients (73%). MU genotypes D, W, and C were found both in environmental and human samples. The micro geo-distribution of MU genotypes from communities showed that genotype D is found both in environmental and human samples, while genotypes W and C are specific to environmental samples and human lesions, respectively. No obvious focal grouping of MU genotypes was observed at the community scale. An additional survey in the human microhabitat suggests that domestic and wild animals do not shed MU in their saliva and feces in sampled communities. Conclusions VNTR typing uncovered different MU genotypes circulating in the endemic communities of the Akonolinga district. A MU environmental genotype was found in patients, yet the mechanism of contamination remains to be investigated; and recovering MU in culture from the environment remains key priority to enable a better understanding of the mode of transmission of BU. We also conclude that excretions from suspected animals are unlikely to be major sources of MU in the Nyong Valley in Cameroon.

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