Ultra-short-course and intermittent TB47-containing oral regimens produce stable cure against Buruli ulcer in a murine model and prevent the emergence of resistance for Mycobacterium ulcerans

Buruli ulcer(BU),caused by Mycobacterium ulcerans,is currently treated with rifampin estreptomycin or rifampineclarithromycin daily for 8 weeks recommended by World Health Organization(WHO).These options are lengthy with severe side effects.A new anti-tuberculosis drug,TB47,targeting QcrB in cytochrome bc1:aa3 complex is being developed in China.TB47-containing regimens were evaluated in a well-established murine model using an autoluminescent M.ulcerans strain.Highlevel TB47-resistant spontaneous M.ulcerans mutants were selected and their qcrB genes were sequenced.The in vivo activities of TB47 against both low-level and high-level TB47-resistant mutants were tested in BU murine model.Here,we show that TB47-containing oral 3-drug regimens can completely cure BU in 2 weeks for daily use or in 3 weeks given twice per week(6 doses in total).All high-level TB47-resistant mutants could only be selected using the low-level mutants which were still sensitive to TB47 in mice.This is the first report of double mutations in QcrB in mycobacteria.In summary,TB47-containing regimens have promise to cure BU highly effectively and prevent the emergence of drug resistance.Novel QcrB mutations found here may guide the potential clinical molecular diagnosis of resistance and the discovery of new drugs against the high-level resistant mutants.

ONIOM Method Characterization of Hydrogen Bonding Sites of Mycolactone A/B, a Buruli Ulcer Toxin

Mycolactone molecules are responsible of Buruli ulcer disease. In this work, we are interested in the geometric, energetic and spectroscopic characterization of the hydrogen bonding interactions in mycolactone A/B, using quantum chemical method, especially ONIOM(HF/6-311+G(d,p):AM1) and ONIOM (B3LYP/6-311+G(d,p):AM1) levels. ONIOM two layers method has been used because mycolactones compounds are very large, taking into account diffuse and polarization functions are important whenever the matter is intermolecular interactions. Geometric, energetic and spectroscopic parameters of hydrogen bonding reaction on each of the nine oxygen heteroatoms of mycolactone A/B have revealed that the O5sp2 heteroatom is far away the hydrogen bonding site. The identification of such a site constitutes a tool for working out a methodology for the annihilation of the destruction effects of mycolactones.

Buruli ulcer in Nigeria:results of a pilot case study in three rural districts

Background:Buruli ulcer(BU),also known as Mycobacterium ulcerans disease,is the third most common mycobacterial disease worldwide.Although BU disease has been diagnosed among Nigerians in neighbouring West African countries,data on the burden of the disease in Nigeria itself are scanty.This study aimed to assess the magnitude and epidemiology of BU in the South South region of Nigeria.Methods:We conducted a cross-sectional survey in the Ogoja territory(comprising 31 communities).We undertook sensitisation programmes centred on BU in 10 of the communities.Participants were asked to identify community members with long-standing ulcers,who were then invited for evaluation.We also contacted traditional healers to refer their clients who had non-healing ulcers.All suspected cases had a full clinical evaluation and laboratory testing.Confirmed cases were given treatment in a referral hospital in the territory.Results:We diagnosed 41 clinical BU cases;36(87.8%)of which were confirmed by quantitative polymerase chain reaction(qPCR).These 36 PCR-confirmed cases were diagnosed in a total population of 192,169 inhabitants.Therefore,the estimated crude prevalence of BU was 18.7 per 100,000 population,varying from 6.0 to 41.4 per 100,000 in the districts surveyed.The majority(66.7%)of the cases were females.About 92%of the BU lesions were located on the patients’extremities.No differences were observed between the sexes in terms of the location of the lesions.The age of the patients ranged from four to 60 years,with a median age of 17 years.All 35(100%)patients who consented to treatment completed chemotherapy as prescribed.Of the treated cases,29(82.9%)needed and received surgery.All cases healed,but 29(82.9%)had some limitations in movement.Healing with limitations in movement occurred in 18/19(94.7%)and 8/10(80.0%)of patients with lesions>15 cm(Category III)and 6–15 cm in diameter(Category II),respectively.The median duration of treatment was 130(87–164)days for children and 98(56–134)days for adults(p=0.15).Conclusions:In Nigeria,BU is endemic but its severity is underestimated—at least in the study setting.There is a need to identify and map BU endemic regions in Nigeria.A comprehensive BU control programme is also urgently needed.