Leprostatic agent

Abstract: Thioamide drugs, ethionamide (ETH) and prothionamide (PTH), are clinically effective in the treatment of Mycobacterium tuberculosis, M. leprae, and M. avium complex infections. Although generally considered second-line drugs for tuberculosis, their use has increased considerably as the number of multidrug resistant and extensively drug resistant tuberculosis cases continues to rise. Despite the widespread use of thioamide drugs to treat tuberculosis and leprosy, their precise mechanisms of action remain unknown. Using a cell-based activation method, we now have definitive evidence that both thioamides form covalent adducts with nicotinamide adenine dinucleotide (NAD) and that these adducts are tight-binding inhibitors of M. tuberculosis and M. leprae InhA. The crystal structures of the inhibited M. leprae and M. tuberculosis InhA complexes provide the molecular details of target–drug interactions. The purified ETH-NAD and PTH-NAD adducts both showed nanomolar Kis against M. tuberculosis and M. leprae InhA. Knowledge of the precise structures and mechanisms of action of these drugs provides insights into designing new drugs that can overcome drug resistance.

Abstract: Objective To determine the effectiveness of chemoprophylaxis using a single dose of rifampicin to prevent leprosy in close contacts. Design Single centre, double blind, cluster randomised, placebo controlled trial. SettingLeprosy control programme in two districts of northwest Bangladesh with a population of more than four million. Participants28 092 close contacts of 1037 patients with newly diagnosed leprosy. 21 711 contacts fulfilled the study requirements. Interventions A single dose of rifampicin or placebo given to close contacts in the second month of starting the index patient’s treatment, with follow-up for four years. Main outcome measure Development of clinical leprosy. Results 18 869 of the 21 711 contacts (86.9%) were followed-up at four years. Ninety one of 9452 contacts in the placebo group and 59 of 9417 in the rifampicin group had developed leprosy. The overall reduction in incidence of leprosy using a single dose of rifampicin in the first two years was 57% (95% confidence interval 33% to 72%). The groups did not differ between two and four years. The overall number needed to treat (NNT) to prevent a single case of leprosy among contacts was 297 (95% confidence interval 176 to 537). Differences were found between subgroups at two years, both in reduction of incidence and in NNT. ConclusionA single dose of rifampicin given to contacts of patients with newly diagnosed leprosy is effective at preventing the development of clinical leprosy at two years. The effect was maintained, but no difference was seen between the placebo and rifampicin groups beyond two years. Trial registration Current Controlled Trials ISRCTN61223447.

Abstract: Sequences of the folP1, rpoB, and gyrA genes were analyzed for 88 isolates of Mycobacterium leprae from leprosy patients in Japan, Haiti, Indonesia, Pakistan, and the Philippines. Thirteen isolates (14.8%) showed representative mutations in more than two genes, suggesting the emergence of multidrug-resistant M. leprae.

Abstract: Leprosy is an infectious disease that has now been reported for more than 2000 years. The leprosy elimination goal set by the World Health Organization (WHO), i.e. a global prevalence rate <1 patient per 10,000 population, was achieved in the year 2000, but more than 200,000 new case patients are still reported each year, particularly in India, Brazil, and Indonesia. Leprosy is a specific infection: (i) it is a chronic infection primarily affecting the skin and peripheral nerves, (ii) Mycobacterium leprae is one of the last bacterial species of medical interest that cannot be cultured in vitro (mainly because of its reductive genome evolution), and (iii) transmission and pathophysiological data is still limited. The various presentations of the disease (Ridley-Jopling and WHO classifications) are correlated with the patient's immune response, bacillary load, and by the delay before diagnosis. Multidrug therapy (dapsone, rifampicin, with or without clofazimine) has been recommended since 1982 as the standard treatment of leprosy; 6 months for patients presenting with paucibacillary leprosy and 12 months for patients presenting with multibacillary leprosy. The worldwide use of leprosy drugs started in the 1980s and their free access since 1995 contributed to the drastic decline in the number of new case patients. Resistant strains are however emerging despite the use of multidrug therapy; identifying and monitoring resistance is still necessary.