Mechanism of thioamide drug action against tuberculosis and leprosy.

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.

[Multi-drug therapy trials for leprosy in Senegal: first observations relative to liver tolerance of multibacillary patients. Therapeutic consequences]. / Essais de polychimiothérapie de la lèpre au Sénégal: premières observations relatives à la tolérance hépatique des maladies multibacillaires--conséquences thérapeutiques.

The authors have studied tolerance of multibacillary patients to 4 MDT regimens. These 4 regimens consist of: One supervised part in which RMP-ETH combination in once-monthly administered; furthermore, in 2 of these regimens, is included one "starter phase" with daily doses of that combination for 2 months. One self-administered part during which CLO is associated either to DDS for new cases, or to ETH for relapses. Clinical Supervision: Out to 310 multibacillary patients, 7 cases of hepatitis with or without icterus, but no death due to the treatment. Interruptions of MDT have been temporary and have been observed in 0.9 to 5.6% of the patients according to the therapeutic regimen. Checking SGOT: The SGOT were abnormally high in 16.3% of the patients before treatment. These pre-existing liver damages do not favour the appearance of intolerance disorders. During MDT, abnormal increases in SGOT are observed in 27% of the patients but there is no exact correlation between the absorbed doses of ETH and the frequency in SGOT increases. The clinical or biological evidence of liver damages occur rather early (1st, 2nd month) in regimens with "starter phase", and later (4th-8th month) in those without "starter phase". But introduction of "Starter phase" does not increase the global frequency of such intolerance accidents. ETH combined with RMP, must be used under steady clinical and biological supervision. Recalling the results of a previous survey, the authors consider that a long duration of MDT is not necessary. For the multibacillary leprosy treatment, they propose a diphasic regimen, more easily applicable in the field than the WHO protocols. In this diphasic regimen, the only part which must be supervised is the initial "starter phase" of 2 month. It consists of daily administration of 3 antibacillary drug among which RMP and ETH. The second phase is a relay treatment using 2 drugs, CLO combined with DDS or ETH, self-administered until smear negativity.

Synergistic effect of rifampin, streptomycin, ethionamide, and ethambutol on Mycobacterium intracellulare

A method of quantitative estimation to determine the interaction of antituberculosis drugs is suggested. The design of experiments, performed on 7H11 agar plates, is adjusted to the following statistical treatment by combined use of probit analysis and isobologram methods. By plotting the values reflecting the inhibition of 75% of the bacterial population (ED75) with their confidence limits on the isobologram, it was found that the clearest results proving synergism between the drugs could be obtained. Six 2-drug combinations and 6 3-drug combinations were tested against strains of Mycobacterium intracellulare (serovar 8), and a synergistic effect was demonstrated in most of them. These were various combinations of rifampin, streptomycin, ethambutol, and ethionamide. The application of probit analysis to the data derived from testing single drugs can provide a quantitative estimation of the actual drug resistance of the M. intracellulare strains.

[Sensitivity to dapsone, sulfamethoxypyridazine and ethionamide of mycobacterium leprae taken from patients treated by the drugs]. / Sensibilité envers la dapsone, la sulfamethoxypyridazine et l'éthionamide, de Mycobacterium leprae provenant de malades traités par ces substances

Suspensions of M. leprae from skin biopsies of patients treated with dapsone (DDS) (four cases), sulfamethoxypyridazine (SMP) (six cases), and ethionamide (ETH) (seven cases), were inoculated into mouse foot pads and their sensitivity for the different drugs determined. Two strains were DDS resistant. Resistance appeared after 13 and 14 years respectively after the start of treatment. Five strains were isolated from patients treated with SMP. Relapses during sulfonamide treatment are considered to be due to the low effective serum concentrations reached by SMP, a situation which is aggravated by irregularities in drug intake. Fortunately all strains were sensitive to SMP and DDS as well. Four strains were ETH resistant. ETH resistance at the present moment reaches 4% and appeared in two cases six years after the start of treatment. It is concluded that SMP is not indicated for the treatment of multibacillary leprosy and that ETH can be used only in association with other drugs during the introductory phase of treatment of multibacillary forms of leprosy.

A radiometric method for predicting effectiveness of chemotherapeutic agents in murine leprosy.

A simple radiometric method has been developed for evaluating the effect of drugs on the metabolism of M. lepraemurium. The method is based on the measurement of the 14CO2 produced through bacterial metabolism of acetate-U-14C. Seventeen drugs were tested: bacitracin, cephaloridine, chloramphenicol, cycloserine, dactinomycin, DDS, ethionamide, INH, kanamycin, methenamine mandelate, nitrofurantoin, oxacillin, polymyxin B, rifampicin, streptomycin, sulfadimethoxine and vancomycin. The drugs which caused most marked inhibition were chloramphenicol, INH, ethionamide and nitrofurantoin in order of increasing effectiveness. The radiometric study which is completed in 15 days permits direct study of the drug effect on the metabolism of M. lepraemurium and a more rapid screening of antileprosy drugs than has previously been possible. Currently, these observations are being extended to studies of the structure-activity relationships of antileprosy drugs and the metabolism and drug susceptibility of M. leprae in vitro.