Antitubercular Activity of Disulfiram, an Antialcoholism Drug, against Multidrug- and Extensively Drug-Resistant Mycobacterium tuberculosis Isolates

Abstract

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...

Potential antimicrobial agents for the treatment of multidrug-resistant tuberculosis

“…The MIC90 (MIC required to inhibit growth of 90% of organisms) of DSF and DDC against clinical isolates were 1.56 and 3.13 mg?mL -1 , respectively. They also showed bactericidal activity against intracellular M. tuberculosis in human monocyte leukaemia cell line (THP-1) at 6-30 mg?mL -1 and 10-30 mg?mL -1 , respectively [35]. Since no cross resistance of DSF and DDC with other antituberculous drugs was observed, these compounds may be of potential value for future regimens against MDR/XDR-TB [35].…”

“…DSF and DDC exhibit growth-inhibitory activity against bacteria, fungi, protozoa and viruses. DSF is effective against MDR/XDR-TB and exhibits bactericidal activity in vivo and in vitro [35]. The mechanism of action of DDC against M. tuberculosis has been reported as inhibition of b-class carbonic anhydrases from M. tuberculosis [78].…”

“…In vivo studies DSF kills M. tuberculosis at 80-160 mg?kg -1 in a mouse model with chronic TB [35]. DDC enhances the activity of pyrazinamide and rifampicin twofold when co-administered in mice at 100 mg?kg -1 , showing activity against persisters of M. tuberculosis [33].…”

“…DSF is a prodrug and is enzymatically metabolised in the blood to metabolites, primarily diethyldithiocarbamate (DDC or DETC) within 4 min [33,35]. DSF and DDC exhibit growth-inhibitory activity against bacteria, fungi, protozoa and viruses.…”

Boronic-aurone Derivatives as Anti-Tubercular Agents: Design, Synthesis and Biological Evaluation

“…To underscore the importance of this approach, the first FDA approved antitubercular drug in over 40 years, bedaquiline [33], and others in advanced clinical development (Delamanid, Sutezolid and SQ109) were discovered through phenotypic screening [34,35]. It appears that no truly new anti-TB lead have successful emerged from target-based discovery approach.…”