Ever since the first report from Australia in 1948, followed by many publications from Uganda and Congo, the only treatment for the emerging infectious disease now known as Buruli ulcer, caused by Mycobacterium ulcerans and affecting mainly children in swampy areas of tropical countries, was prolonged surgery, i.e., excision and skin grafting. In the past few years, our laboratory revived the mouse footpad model of M. ulcerans disease and demonstrated that treatment for two months with amikacin (or streptomycin) and rifampin, used in the mouse at doses equipotent to human doses, was highly active (bactericidal). Clinical trials have since demonstrated that, when administered to humans, the same drug combination is also very active. Surgery was avoided in almost half of the cases and facilitated in the remaining cases. Because of the practical inconvenience, the risk of toxicity and accidental viral transmission through daily injections of aminoglycoside, our main objective is to develop a totally oral drug regimen of Buruli ulcer and to search for an active preventive treatment. To address these issues, our first aim is to create a M. ulcerans containing luxAB reporter gene in order to overcome the difficulties related to the slow growth of M. ulcerans in vivo (division time 3-5 days),and its relatively poor and lengthy growth in vitro.
Our second aim i s to test the ability of the new recombinant M. ulcerans to produce toxin (because of the relative instabilty of mycolactone-encoding genes in the plasmid ) and virulence for the mouse, and its validity for rapid in vitro and in vivo assessment of drug susceptibility in comparison with standard models. Because all drugs tested to date, with the exception of aminoglycosides and rifampin, have only bacteriostatic activity against M. ulcerans, our third aim is to systematically screen for novel in vitro and in vivo active drugs and drug combinations using the new lux-containing M. ulcerans. Applying the standard rule in public health "prevention is better than cure", our fourth aim is to test the validity of the recombinant M. ulcerans for vaccine assessment and compare the efficacy of BCG, DNA vaccines and newly proposed vaccines in the prevention of M. ulcerans disease. The main experimental model we propose to use is the mouse footpad model of experimental chemotherapy of M. ulcerans disease because the results obtained with this model have proved to be predictive of results in humans.
Our proposal, Firing up new treatments against Mycobacterium ulcerans disease (Buruli ulcer), endeavors to use well-established mouse models of M. ulcerans disease to indicate new or improved preventative and curative methods for a devastating, emerging, neglected tropical disease. The disease now has higher prevalence than leprosy and/or tuberculosis in some regions of West African countries (notably, Ghana and Benin). Previous work has already succeeded in identifying treatment regimens that can replace or reduce surgery and skin grafting whereas we now seek to identify completely oral treatments to replace injected antibiotics.
|Converse, Paul J; Xing, Yalan; Kim, Ki Hyun et al. (2014) Accelerated detection of mycolactone production and response to antibiotic treatment in a mouse model of Mycobacterium ulcerans disease. PLoS Negl Trop Dis 8:e2618|
|Sarfo, Fred Stephen; Converse, Paul J; Almeida, Deepak V et al. (2013) Microbiological, histological, immunological, and toxin response to antibiotic treatment in the mouse model of Mycobacterium ulcerans disease. PLoS Negl Trop Dis 7:e2101|
|Zhang, Tianyu; Li, Si-Yang; Nuermberger, Eric L (2012) Autoluminescent Mycobacterium tuberculosis for rapid, real-time, non-invasive assessment of drug and vaccine efficacy. PLoS One 7:e29774|
|Converse, Paul J; Nuermberger, Eric L; Almeida, Deepak V et al. (2011) Treating Mycobacterium ulcerans disease (Buruli ulcer): from surgery to antibiotics, is the pill mightier than the knife? Future Microbiol 6:1185-98|
|Zhang, Tianyu; Li, Si-Yang; Converse, Paul J et al. (2011) Using bioluminescence to monitor treatment response in real time in mice with Mycobacterium ulcerans infection. Antimicrob Agents Chemother 55:56-61|
|Almeida, Deepak; Converse, Paul J; Ahmad, Zahoor et al. (2011) Activities of rifampin, Rifapentine and clarithromycin alone and in combination against mycobacterium ulcerans disease in mice. PLoS Negl Trop Dis 5:e933|
|Converse, Paul J; Almeida, Deepak V; Nuermberger, Eric L et al. (2011) BCG-mediated protection against Mycobacterium ulcerans infection in the mouse. PLoS Negl Trop Dis 5:e985|
|Zhang, Tianyu; Bishai, William R; Grosset, Jacques H et al. (2010) Rapid assessment of antibacterial activity against Mycobacterium ulcerans by using recombinant luminescent strains. Antimicrob Agents Chemother 54:2806-13|