The antimycobacterial activities of disulfiram (DSF) and diethyldithiocarbamate (DDC) against multidrug-and extensively drug-resistant tuberculosis (MDR/XDR-TB) clinical isolates were evaluated in vitro. Both DSF and DDC exhibited potent antitubercular activities against 42 clinical isolates of M. tuberculosis, including MDR/XDR-TB strains. Moreover, DSF showed remarkable bactericidal activity ex vivo and in vivo. Therefore, DSF might be a drug repurposed for the treatment of MDR/XDR-TB. According to the updated guidelines of the World Health Organization, the medications effective against multidrug-and extensively drug-resistant tuberculosis (MDR/XDR-TB) are confined because only a limited selection of drugs is available; therefore, the development of novel or repurposed drugs with activity against MDR/XDR-TB is strongly desired (9). Disulfiram (DSF; tetraethyl thiuram disulfide) has been used orally in the clinical treatment of alcoholism since 1949 and has been proven to exert an inhibitory effect on aldehyde dehydrogenase in vivo with 80% bioavailability and established safety profiles (13, 33). Both DSF and its first metabolite, diethyldithiocarbamate (DDC), were reported to exhibit growth-inhibitory activity against bacteria, fungi, protozoa, and viruses (2,18,23,26,27). In the mid-1950s, the tuberculostatic effects of DSF and DDC were demonstrated in vivo using guinea pigs (17). Subsequently, it was reported that DDC enhances monocyte-induced antitubercular activity in both healthy volunteers and human immunodeficiency virus-infected patients ex vivo (16). Recently, the antitubercular activities of DDC and the nitric oxide synthase inhibitor pyrrolidine dithiocarbamate (PDTC) against nonreplicating Mycobacterium tuberculosis have been demonstrated (4). In addition, we reported the unique antimycobacterial activities of dithiocarbamates and also the potent antitubercular activities of compounds containing dithiocarbamate groups, such as dimethyldithiocarbamate (DMDC), DDC, and PDTC (14,15). More recently, the mode of action of dithiocarbamates against M. tuberculosis has been reported to be through ␤-class carbonic anhydrases (␤-CAs), which are considered possible drug targets (19). However, the mechanism of action of DSF remains unknown.In the present study, we evaluated the antimycobacterial activities of DSF and its metabolites against M. tuberculosis, including MDR/XDR-TB clinical isolates, in more detail. Furthermore, the intracellular bactericidal activities of these compounds against a virulent strain, M. tuberculosis H 37 Rv, within macrophages were examined ex vivo, and the bactericidal activity of DSF in vivo was determined using the mouse model of chronic TB. Finally, the mechanisms of action of these compounds were investigated by means of gene-overexpressing strains in vitro. MATERIALS AND METHODSBacterial strains. M. tuberculosis H 37 Rv ATCC 25618, M. tuberculosis H 37 Ra ATCC 25177, Mycobacterium avium ATCC 25291, and M. avium ATCC 35718 were purchased from the American Type Culture Collect...

Optimal doses for antituberculosis (anti-TB) drugs in children have yet to be established. In 2010, the World Health Organization (WHO) recommended revised dosages of the first-line anti-TB drugs for children. Pharmacokinetic (PK) studies that investigated the adequacy of the WHO revised dosages to date have yielded conflicting results. We performed population PK modeling using data from one of these studies to identify optimal dosage ranges. Ghanaian children with tuberculosis on recommended therapy with rifampin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) for at least 4 weeks had blood samples collected predose and at 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography-mass spectrometry methods. Nonlinear mixed-effects models were applied to describe the population PK of those drugs using MonolixSuite2016R1 (Lixoft, France). Bayesian estimation was performed, the correlation coefficient, bias, and precision between the observed and predicted areas under the concentration-time curve (AUCs) were calculated, and Bland-Altman plots were analyzed. The population PK of RIF and PZA was described by a one-compartment model and that for INH and EMB by a two-compartment model. Plasma maximum concentration () and AUC targets were based on published results for children from India. The lowest target values for pediatric TB patients were attainable at the WHO-recommended dosage schedule for RIF and INH, except for -acetyltransferase 2 non-slow acetylators (rapid and intermediate acetylators) in the lower-weight bands. However, higher published adult targets were not attainable for RIF and INH. The targets were not achieved for PZA and EMB. (This study has been registered at ClinicalTrials.gov under identifier NCT01687504.).

bWe evaluated the antituberculosis (anti-TB) activity of five ␤-lactams alone or in combination with ␤-lactamase inhibitors against 41 clinical isolates of Mycobacterium tuberculosis, including multidrug-resistant and extensively drug-resistant strains. Of those, tebipenem, an oral carbapenem, showed the most potent anti-TB activity against clinical isolates, with a MIC range of 0.125 to 8 g/ml, which is achievable in the human blood. More importantly, in the presence of clavulanate, MIC values of tebipenem declined to 2 g/ml or less.

Predicting drug-drug interactions (DDIs) related to cytochrome P450 (CYP), such as CYP3A4 and one of the major drug transporters, P-glycoprotein (P-gp), is crucial in the development of future chemotherapeutic regimens to treat tuberculosis (TB) and TB/AIDS coinfection cases. We evaluated the effects of 30 anti-TB drugs, novel candidates, macrolides, and representative antiretroviral drugs on human CYP3A4 activity using a commercially available screening kit for CYP3A4 inhibitors and a human hepatocyte, HepaRG. Moreover, in order to estimate the interactions of these drugs with human P-gp, screening for substrates was performed. For some substrates, P-gp inhibition tests were carried out using P-gp-expressing MDCK cells. As a result, almost all the compounds showed the expected effects on human CYP3A4 both in the in vitro screening and in HepaRG cells. Importantly, the unproven mechanisms of DDIs caused by WHO group 5 drugs, thioamides, and p-aminosalicylic acid were elucidated. Intriguingly, clofazimine (CFZ) exhibited weak inductive effects on CYP3A4 at >0.25 M in HepaRG cells, while an inhibitory effect was observed at 1.69 M in the in vitro screening, suggesting that CFZ autoinduces CYP3A4 in the human liver. Our method, based on one of the pharmacokinetics parameters in humans, provides more practical information associated with not only DDIs but also with drug metabolism.