scholarly journals Hosts and transmission of Mycobacterium ulcerans: a systematic review

2021 ◽  
Vol 22 (4) ◽  
pp. 439-447
Author(s):  
I.F. Aboagye
Keyword(s):  
Research Question ◽  
Buruli Ulcer ◽  
Aquatic Organisms ◽  
Mycobacterium Ulcerans ◽  
Future Research ◽  
Pubmed Database ◽  
Mode Of Transmission ◽  
Living Organisms ◽  
Aquatic Bugs

The control of Buruli ulcer (BU), a debilitating neglected tropical disease, is hampered by the inadequate understanding of the mode of transmission of its causative agent, Mycobacterium ulcerans (M. ulcerans). The DNA of M. ulcerans has been detected in some living organisms and non-living environmental samples of both aquatic and terrestrial sources. However, it is unclear whether the identified organisms support in vivo multiplication of the bacterium or play any role in its transmission. This paper identifies hosts of M. ulcerans, reviews progress made in unravelling the exact mode of transmission of M. ulcerans and identifies research gaps in this aspect of BU epidemiology. Using the search terms, ‘niche, Mycobacterium ulcerans’ and ‘mode of transmission, Mycobacterium ulcerans’ as well as defined inclusion criteria, information was obtained from the PubMed database and reviewed to assess their importance to the research question. Aquatic bugs of the genera Appasus and Diplonychus as well as Naucoris cimicoides and possums were identified to support in vivo multiplication of the bacterium. Bite of M. ulcerans contaminated Aedes notoscriptus, bite of aquatic bugs harboring or contaminated with M. ulcerans, and M. ulcerans contaminated skin-puncturing materials present in nature create opportunity for its transmission and infection. Appropriate protective measures may be useful to reduce the risk of exposure to M. ulcerans in BU endemic areas, and incorporation of trophic interactions of aquatic organisms known to support in vivo multiplication of M. ulcerans is needed in future research for better understanding of the spread of M. ulcerans in nature. French title: Hôtes et transmission de Mycobacterium ulcerans: une revue systématique   Le contrôle de l'ulcère de Buruli (UB), une maladie tropicale négligée débilitante, est entravé par la compréhension insuffisante du mode de transmission de son agent causal, Mycobacterium ulcerans (M. ulcerans). L'ADN de M. ulcerans a été détecté dans certains organismes vivants et des échantillons environnementaux non vivants de sources aquatiques et terrestres. Cependant, il n'est pas clair si les organismes identifiés favorisent la multiplication in vivo de la bactérie ou jouent un rôle dans sa transmission. Cet article identifie les hôtes de M. ulcerans, passe en revue les progrès réalisés pour démêler le mode exact de transmission de M. ulcerans et identifie les lacunes de la recherche dans cet aspect de l'épidémiologie de l'UB. À l'aide des termes de recherche « niche, Mycobacterium ulcerans » et « mode de transmission, Mycobacterium ulcerans » ainsi que des critères d'inclusion définis, des informations ont été obtenues à partir de la base de données PubMed et examinées pour évaluer leur importance pour la question de recherche. Des punaises aquatiques des genres Appasus et Diplonychus ainsi que Naucoris cimicoides et possums ont été identifiées pour soutenir la multiplication in vivo de la bactérie. La piqûre d'Aedes notoscriptus contaminé par M. ulcerans, la piqûre d'insectes aquatiques hébergeant ou contaminés par M. ulcerans et les matériaux de perforation de la peau contaminés par M. ulcerans présents dans la nature créent une opportunité de transmission et d'infection. Des mesures de protection appropriées peuvent être utiles pour réduire le risque d'exposition à M. ulcerans dans les zones d'endémie UB, et l'incorporation d'interactions trophiques d'organismes aquatiques connus pour favoriser la multiplication in vivo de M. ulcerans est nécessaire dans les recherches futures pour une meilleure compréhension de la propagation de M. ulcerans dans la nature.  

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.

scholarly journals Heterogeneity of Mycolactones Produced by Clinical Isolates of Mycobacterium ulcerans: Implications for Virulence

2003 ◽  
Vol 71 (2) ◽  
pp. 774-783 ◽  
Author(s):  
Armand Mve-Obiang ◽  
Richard E. Lee ◽  
Françoise Portaels ◽  
P. L. C. Small
Keyword(s):  
Clinical Evidence ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Biologically Active ◽  
In Vivo Studies ◽  
Tissue Destruction ◽  
The Core ◽  
A Minor ◽  
Layer Chromatography

ABSTRACT Mycobacterium ulcerans is the causative agent of Buruli ulcer, a severe necrotizing skin disease endemic in tropical countries. Clinical evidence suggests that M. ulcerans isolates from Asia, Mexico, and Australia may be less virulent than isolates from Africa. In vivo studies suggest that mycolactone, a polyketide-derived macrolide toxin, plays a major role in the tissue destruction and immune suppression which occur in cases of Buruli ulcer. Mycolactones were extracted from 34 isolates of M. ulcerans representing strains from Africa, Malaysia, Asia, Australia, and Mexico. Thin-layer chromatography, mass spectroscopic analysis, and cytopathic assays of partially purified mycolactones from these isolates revealed that M. ulcerans produces a heterogeneous mixture of mycolactone variants. Mycolactone A/B, the most biologically active mycolactone species, was identified by mass spectroscopy as [M+Na]+ at m/z 765.5 in all cytotoxic isolates except for those from Mexico. Mycolactone C [M+Na]+ at m/z 726.3 was the dominant mycolactone species in eight Australian isolates, and mycolactone D [M+Na]+ m/z 781.2 was characteristic of two Asian strains. Mycolactone species are conserved within specific geographic areas, suggesting that there may be a correlation between mycolactone profile and virulence. In addition, the core lactone, [M+Na]+ m/z 447.4, was identified as a minor species, supporting the hypothesis that mycolactones are synthesized by two polyketide synthases. A cytopathic assay of the core lactone showed that this molecule is sufficient for cytotoxicity, although it is much less potent than the complete mycolactone.

scholarly journals Snapshot fecal survey of domestic animals in rural Ghana forMycobacterium ulcerans

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2065 ◽  
Author(s):  
Nicholas J. Tobias ◽  
Nana Ama Ammisah ◽  
Evans K. Ahortor ◽  
John R. Wallace ◽  
Anthony Ablordey ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Buruli Ulcer ◽  
Domestic Animals ◽  
Mycobacterium Ulcerans ◽  
Animal Reservoir ◽  
Rural Ghana ◽  
Reservoir Species ◽  
Mode Of Transmission ◽  
High Concentrations ◽  
Negative Controls

Identifying the source reservoirs ofMycobacterium ulceransis key to understanding the mode of transmission of this pathogen and controlling the spread of Buruli ulcer (BU). In Australia, the native possum can harborM. ulceransin its gastrointestinal tract and shed high concentrations of the bacteria in its feces. To date, an analogous animal reservoir in Africa has not been identified. Here we tested the hypothesis that common domestic animals in BU endemic villages of Ghana are reservoir species analogous to the Australian possum. Using linear-transects at 10-meter intervals, we performed systematic fecal surveys across four BU endemic villages and one non-endemic village in the Asante Akim North District of Ghana. One hundred and eighty fecal specimens from a single survey event were collected and analyzed by qPCR for theM. ulceransdiagnostic DNA targets IS2404and KR-B. Positive and negative controls performed as expected but all 180 test samples were negative. This structured snapshot survey suggests that common domestic animals living in and around humans do not shedM. ulceransin their feces. We conclude that, unlike the Australian native possum, domestic animals in rural Ghana are unlikely to be major reservoirs ofM. ulcerans.

scholarly journals Mycolactone toxin induces an inflammatory response by targeting the IL-1β pathway: Mechanistic insight into Buruli ulcer pathophysiology

2020 ◽  
Vol 16 (12) ◽  
pp. e1009107
Author(s):  
M. Foulon ◽  
M. Robbe-Saule ◽  
J. Manry ◽  
L. Esnault ◽  
Y. Boucaud ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Inflammatory Factors ◽  
Dependent Manner ◽  
Local Inflammatory Response ◽  
Mechanistic Insight ◽  
Insight Into

Mycolactone, a lipid-like toxin, is the major virulence factor of Mycobacterium ulcerans, the etiological agent of Buruli ulcer. Its involvement in lesion development has been widely described in early stages of the disease, through its cytotoxic and immunosuppressive activities, but less is known about later stages. Here, we revisit the role of mycolactone in disease outcome and provide the first demonstration of the pro-inflammatory potential of this toxin. We found that the mycolactone-containing mycobacterial extracellular vesicles produced by M. ulcerans induced the production of IL-1β, a potent pro-inflammatory cytokine, in a TLR2-dependent manner, targeting NLRP3/1 inflammasomes. We show our data to be relevant in a physiological context. The in vivo injection of these mycolactone-containing vesicles induced a strong local inflammatory response and tissue damage, which were prevented by corticosteroids. Finally, several soluble pro-inflammatory factors, including IL-1β, were detected in infected tissues from mice and Buruli ulcer patients. Our results revisit Buruli ulcer pathophysiology by providing new insight, thus paving the way for the development of new therapeutic strategies taking the pro-inflammatory potential of mycolactone into account.

scholarly journals Mycobacterium ulcerans Population Genomics To Inform on the Spread of Buruli Ulcer across Central Africa

mSphere ◽  
2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Koen Vandelannoote ◽  
Delphin Mavinga Phanzu ◽  
Kapay Kibadi ◽  
Miriam Eddyani ◽  
Conor J. Meehan ◽  
...  
Keyword(s):  
Disease Control ◽  
Population Genomics ◽  
Demographic History ◽  
Buruli Ulcer ◽  
Central Africa ◽  
Mycobacterium Ulcerans ◽  
Evolutionary Trajectory ◽  
Content Type ◽  
Mode Of Transmission ◽  
The Impact

ABSTRACT Buruli ulcer is a neglected tropical disease of skin and subcutaneous tissue caused by infection with the pathogen Mycobacterium ulcerans. Many critical issues for disease control, such as understanding the mode of transmission and identifying source reservoirs of M. ulcerans, are still largely unknown. Here, we used genomics to reconstruct in detail the evolutionary trajectory and dynamics of M. ulcerans populations at a central African scale and at smaller geographical village scales. Whole-genome sequencing (WGS) data were analyzed from 179 M. ulcerans strains isolated from all Buruli ulcer foci in the Democratic Republic of the Congo, The Republic of Congo, and Angola that have ever yielded positive M. ulcerans cultures. We used both temporal associations and the study of the mycobacterial demographic history to estimate the contribution of humans as a reservoir in Buruli ulcer transmission. Our phylogeographic analysis revealed one almost exclusively predominant sublineage of M. ulcerans that arose in Central Africa and proliferated in its different regions of endemicity during the Age of Discovery. We observed how the best sampled endemic hot spot, the Songololo territory, became an area of endemicity while the region was being colonized by Belgium (1880s). We furthermore identified temporal parallels between the observed past population fluxes of M. ulcerans from the Songololo territory and the timing of health policy changes toward control of the Buruli ulcer epidemic in that region. These findings suggest that an intervention based on detecting and treating human cases in an area of endemicity might be sufficient to break disease transmission chains, irrespective of other reservoirs of the bacterium. IMPORTANCE Buruli ulcer is a destructive skin and soft tissue infection caused by Mycobacterium ulcerans. The disease is characterized by progressive skin ulceration, which can lead to permanent disfigurement and long-term disability. Currently, the major hurdles facing disease control are incomplete understandings of both the mode of transmission and environmental reservoirs of M. ulcerans. As decades of spasmodic environmental sampling surveys have not brought us much closer to overcoming these hurdles, the Buruli ulcer research community has recently switched to using comparative genomics. The significance of our research is in how we used both temporal associations and the study of the mycobacterial demographic history to estimate the contribution of humans as a reservoir in Buruli ulcer transmission. Our approach shows that it might be possible to use bacterial population genomics to assess the impact of health interventions, providing valuable feedback for managers of disease control programs in areas where health surveillance infrastructure is poor.

scholarly journals Mycobacterium ulceransin Mosquitoes and March flies captured from endemic areas of Northern Queensland, Australia

2018 ◽  
Author(s):  
Avishek Singh ◽  
William John Hannan McBride ◽  
Brenda Govan ◽  
Mark Pearson ◽  
Scott A. Ritchie
Keyword(s):  
Causative Agent ◽  
Buruli Ulcer ◽  
Mycobacterial Infection ◽  
Blood Feeding ◽  
Mycobacterium Ulcerans ◽  
Mechanical Transmission ◽  
Environmental Reservoir ◽  
Nontuberculous Mycobacterial Infection ◽  
Mode Of Transmission ◽  
Endemic Areas

AbstractMycobacterium ulceransis the causative agent of Buruli ulcer (BU). This nontuberculous mycobacterial infection has been reported in over 33 countries worldwide. In Australia, the majority of cases of BU have been recorded in coastal Victoria and the Mossman-Daintree areas of north Queensland. Mosquitoes have been postulated as a vector ofM. ulceransin Victoria, however the specific mode of transmission of this disease is still far from being well understood. In the current study, we trapped and analysed 16,900 (allocated to 845 pools) mosquitoes and 296 March flies from the endemic areas of north Queensland to examine for the presence ofM. ulceransDNA by polymerase chain reaction. Seven of 845 pools of mosquitoes were positive on screening using the IS2404 PCR target but only one pool was positive for presence ofM. ulceransafter confirmatory testing. None of the March fly samples were positive for the presence ofM. ulcerans.M. ulceranswas detected on proboscises of deliberately exposed mosquitoes.Author SummaryThe causative agent of Buruli ulcer is Mycobacterium ulcerans. This destructive skin disease is characterized by extensive and painless necrosis of skin and underlying tissues usually on extremities of body due to production of toxin named mycolactone. The disease is prevalent in Africa and coastal Australia. The exact mode of transmission and potential environmental reservoir for the pathogen still remain obscure. Aquatic and biting insects have been identified as important niche in transmission and maintenance of pathogen in the environment. In this study we screened mosquitoes and march flies captured from endemic areas of northern Queensland for the presence ofM. ulcerans.In addition, we conducted artificial blood feeding experiment to identify the role of mosquitoes in transmission of this pathogen. We found one pool of mosquito out of 845 pools positive forM. ulceransand none of the March fly samples were positive. This could indicate a low burden of the bacteria in the environment coinciding with a comparatively low number of human cases ofM. ulceransinfection seen during the trapping period of the study. Evidence to support mechanical transmission via mosquito proboscises was found.

scholarly journals Immunosenescence in some but not all immune components in a free-living vertebrate, the tree swallow

2007 ◽  
Vol 274 (1612) ◽  
pp. 951-957 ◽  
Author(s):  
Maria G Palacios ◽  
Joan E Cunnick ◽  
David W Winkler ◽  
Carol M Vleck
Keyword(s):  
T Cell ◽  
Immune Function ◽  
Tree Swallow ◽  
Future Research ◽  
Cell Mediated Immunity ◽  
Free Living ◽  
Age Related ◽  
Living Organisms

A wide diversity of free-living organisms show increases in mortality rates and/or decreases in reproductive success with advancing age. However, the physiological mechanisms underlying these demographic patterns of senescence are poorly understood. Immunosenescence, the age-related deterioration of immune function, is well documented in humans and laboratory models, and often leads to increased morbidity and mortality due to disease. However, we know very little about immunosenescence in free-living organisms. Here, we studied immunosenescence in a free-living population of tree swallows, Tachycineta bicolor , assessing three components of the immune system and using both in vivo and in vitro immunological tests. Immune function in tree swallow females showed a complex pattern with age; acquired T-cell mediated immunity declined with age, but neither acquired nor innate humoral immunity did. In vitro lymphocyte proliferation stimulated by T-cell mitogens decreased with age, suggesting that reduced T-cell function might be one mechanism underlying the immunosenescence pattern of in vivo cell-mediated response recently described for this same population. Our results provide the most thorough description of immunosenescence patterns and mechanisms in a free-living vertebrate population to date. Future research should focus on the ecological implications of immunosenescence and the potential causes of variation in patterns among species.

scholarly journals Potential Animal Reservoir of Mycobacterium ulcerans: Systematic Review

2018 ◽  
Author(s):  
Avishek Singh ◽  
John McBride ◽  
Brenda Govan ◽  
Mark Pearson
Keyword(s):  
Systematic Review ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Published Data ◽  
Animal Reservoir ◽  
Permanent Disability ◽  
Route Of Transmission ◽  
The World ◽  
Mode Of Transmission ◽  
Animal Reservoirs

Mycobacterium ulcerans is the causative agent of the Buruli ulcer, also known, in Australia, as Daintree ulcer or Bairnsdale ulcer. This destructive skin disease is characterized by extensive and painless necrosis of the skin and soft tissue with the formation of large ulcers, commonly on the leg or arm. To date, 33 countries with tropical, subtropical and temperate climates in Africa, the Americas, Asia and the Western Pacific have reported cases of Buruli Ulcer. The disease is rarely fatal, although it may lead to permanent disability and/ or disfigurement if not treated appropriately or in time. It is the third most common mycobacterial infection in the world after tuberculosis and leprosy. The precise mode of transmission of M. ulcerans is yet to be elucidated. Nevertheless, it is possible that the mode of transmission varies with different geographical areas and epidemiological settings. The knowledge about the possible route of transmission and potential animal reservoir of M. ulcerans is poorly understood and still remains patchy. We conducted a systematic review with selected key words on PubMed and INFORMIT databases to aggregate available published data on animal reservoirs of M. ulcerans. After certain inclusion and exclusion criteria, a total of 17 studies were included in the review. A variety of animals, e.g rodents, shrews, possums (ringtail and brush tail), horses, dogs, alpacas, koalas and Indian flap-shelled turtles have been recorded as being infected with M. ulcerans around the world. The majority of studies included in this review identified animal reservoirs, either aquatic or terrestrial, as predisposing for the emergence and reemergence of M. ulcerans infection. Taken together, the selected studies in this systematic review and discussed so far, it is clear that exotic wildlife, aquatic animals and native mammals play a significant role as reservoirs for M. ulcerans.

scholarly journals Aquatic Hemiptera in Southwest Cameroon: Biodiversity of Potential Reservoirs of Mycobacterium ulcerans and Multiple Wolbachia Sequence Types Revealed by Metagenomics

Diversity ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 225
Author(s):  
Seraphine N. Esemu ◽  
Xiaofeng Dong ◽  
Achah J. Kfusi ◽  
Catherine S. Hartley ◽  
Roland N. Ndip ◽  
...  
Keyword(s):  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Minor Role ◽  
Freshwater Habitats ◽  
Southwest Region ◽  
Aquatic Bugs ◽  
A Minor ◽  
Taxonomic Studies ◽  
The Tropics ◽  
Sequence Types

Buruli ulcer (BU), caused by Mycobacterium ulcerans, is a neglected tropical disease associated with freshwater habitats. A variety of limnic organisms harbor this pathogen, including aquatic bugs (Hemiptera: Heteroptera), which have been hypothesized to be epidemiologically important reservoirs. Aquatic Hemiptera exhibit high levels of diversity in the tropics, but species identification remains challenging. In this study, we collected aquatic bugs from emerging foci of BU in the Southwest Region of Cameroon, which were identified using morphological and molecular methods. The bugs were screened for mycobacterial DNA and a selection of 20 mycobacteria-positive specimens from the families Gerridae and Veliidae were subjected to next-generation sequencing. Only one individual revealed putative M. ulcerans DNA, but all specimens contained sequences from the widespread alpha-proteobacterial symbiont, Wolbachia. Phylogenetic analysis placed the Wolbachia sequences into supergroups A, B, and F. Circularized mitogenomes were obtained for seven gerrids and two veliids, the first from these families for the African continent. This study suggests that aquatic Hemiptera may have a minor role (if any) in the spread of BU in Southwest Cameroon. Our metagenomic analysis provides new insights into the incursion of Wolbachia into aquatic environments and generated valuable resources to aid molecular taxonomic studies of aquatic Hemiptera.

scholarly journals In Vitro and In Vivo Activities of Rifampin, Streptomycin, Amikacin, Moxifloxacin, R207910, Linezolid, and PA-824 against Mycobacterium ulcerans

2006 ◽  
Vol 50 (6) ◽  
pp. 1921-1926 ◽  
Author(s):  
Baohong Ji ◽  
Sébastien Lefrançois ◽  
Jerome Robert ◽  
Aurélie Chauffour ◽  
Chantal Truffot ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Potential Toxicity ◽  
Peak Serum Level ◽  
Bactericidal Effects ◽  
The Mean ◽  
The Cost

ABSTRACT Seven antimicrobials were tested in vitro against 29 clinical isolates of Mycobacterium ulcerans. R207910 demonstrated the lowest MIC50 and MIC90, followed by moxifloxacin (MXF), streptomycin (STR), rifampin (RIF), amikacin (AMK), linezolid (LZD), and PA-824. All but PA-824 demonstrated an MIC90 significantly less than the clinically achievable peak serum level. Administered as monotherapy to mice, RIF, STR, AMK, MXF, R207910, and LZD demonstrated some degree of bactericidal activity, whereas PA-824 failed to prevent mortality and to reduce the mean number of CFU in the footpads. Because 4 or 8 weeks of treatment by the combinations RIF-MXF, RIF-R207910, and RIF-LZD displayed bactericidal effects similar to those of RIF-STR and RIF-AMK, these three combinations might be considered as orally administered combined regimens for treatment of Buruli ulcer. Taking into account the cost, potential toxicity, and availability, the combination RIF-MXF appears more feasible for application in the field; additional experiments with mice are warranted to define further its activity against M. ulcerans. In addition, a pilot clinical trial is proposed to test the efficacy of RIF-MXF for treatment of Buruli ulcer.

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