Efficacy of Disulfiram Against Drug Resistant Mycobacterium Abscessus Clinical Isolates

Rationale: Mycobacterium abscessus, a nontuberculous mycobacterium, is an emerging pathogen among patients with cystic fibrosis and bronchiectasis. It causes serious infections in the lungs, soft tissues and skin, and is difficult to treat with current antibiotics. Over the course of M. abscessus infection in patients, the strain often becomes resistant to clinically utilized drugs. Disulfiram, a drug that has been utilized as an oral alcohol deterrent in humans, has been previously identified to exhibit potent growthinhibitory activity against non-tuberculous mycobacteria. This study aims to further assess disulfiram's activity against resistant strains of M. abscessus and its in vivo potential using a novel mouse model of chronic M. abscessus pulmonary infection. Methods: Antibacterial susceptibility testing was conducted via resazurin microplate assay (REMA) to test disulfiram's antimicrobial activity against M. abscessus reference strain ATCC 19977 and a series of M. abscessus clinical strains isolated longitudinally over several years from patients. Using REMA and fractional inhibitory concentration (FIC) index scores, disulfiram's interactions with clinically utilized drugs for M. abscessus infections was tested. Finally, a C57BL/6NJ mouse model of intratracheal M. abscessus pulmonary infection was developed to assess disulfiram in vivo activity. Results: Disulfiram demonstrated similar antimicrobial activity as amikacin, a drug -of-choice to treat M. abscessus infections, against M. abscessus reference strain ATCC 19977. As shown in table 1, disulfiram was active against several amikacin-susceptible (stains B1, D1 & D11) and amikacin-resistant (stains B5 & D10) clinical isolates with minimum inhibitory concentration (MIC) ranging from 8-32 micrograms/mL. Disulfiram was active against multi-drug resistant strains (B8 & MRD4) of M. abscessus, exhibiting similar MICs as drug-susceptible strains. Disulfiram, when used in combination treatment with other anti-NTM drugs, did not show antagonistic activity together with amikacin, vancomycin, bedaquiline, and clofazimine. The in vivo efficacy of disulfiram is currently being assessed using a chronic mouse model with little to no dissemination in the extrapulmonary organs, similar to pulmonary M. abscessus infections in patients. Conclusion: These results show that disulfiram is effective against drug resistant clinical isolates from patients that are resistant to amikacin, a standard drug used to treat M. abscessus. Disulfiram is safe to use with common M. abscessus drugs as it does not have antagonistic activity with these clinical drugs. We are further investigating in vivo activity of disulfiram against M. abscessus pulmonary infection in a mouse model that replicates chronic pulmonary infection in humans.