Auranofin Activity Exposes Thioredoxin Reductase as a Viable Drug Target in Mycobacterium abscessus

被引：16

作者：

Ruth, Mike Marvin ^{[1
]}

van Rossum, Mara ^{[1
]}

Koeken, Valerie A. C. M. ^{[2
]}

Pennings, Lian J. ^{[1
]}

Svensson, Elin M. ^{[3
,4
]}

Ruesen, Carolien ^{[1
]}

Bowles, Edmee C. ^{[1
]}

Wertheim, Heiman F. L. ^{[1
]}

Hoefsloot, Wouter ^{[5
]}

van Ingen, Jakko ^{[1
]}

机构：

[1] Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, Radboud Ctr Infect Dis, Nijmegen, Netherlands

[2] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, Radboud Ctr Infect Dis, Nijmegen, Netherlands

[3] Radboud Univ Nijmegen, Med Ctr, Dept Pharm, Radboud Ctr Infect Dis, Nijmegen, Netherlands

[4] Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden

[5] Radboud Univ Nijmegen, Med Ctr, Dept Pulm Dis, Radboud Ctr Infect Dis, Nijmegen, Netherlands

来源：

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY | 2019年 / 63卷 / 09期

关键词：

drug discovery; drug susceptibility; mycobacteria; Mycobacterium abscessus; pharmacodynamics; MECHANISM; AMIKACIN; DISEASE; KEGG;

D O I：

10.1128/AAC.00449-19

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

Nontuberculous mycobacteria (NTM) are highly drug-resistant, opportunistic pathogens that can cause pulmonary disease. The outcomes of the currently recommended treatment regimens are poor, especially for Mycobacterium abscessus. New or repurposed drugs are direly needed. Auranofin, a gold-based antirheumatic agent, was investigated for Mycobacterium tuberculosis. Here, we test auranofin against NTM in vitro and ex vivo. We tested the susceptibility of 63 NTM isolates to auranofin using broth microdilution. Next, we assessed synergy between auranofin and antimycobacterial drugs using the checkerboard method and calculated the fractional inhibition concentration index (FICI). Using time-kill kinetics assays (TK), we assessed pharmacodynamics of auranofin alone and in combination with drug combinations showing the lowest FICIs for M. abscessus CIP 104536. A response surface analysis was used to assess synergistic interactions over time in TKs. Primary isolated macrophages were infected with M. abscessus and treated with auranofin. Finally, using KEGG Orthology, we looked for orthologues to auranofins drug target in M. tuberculosis. M. abscessus had the lowest auranofin MIC50 (2 mu g/ml) among the tested NTM. The lowest average FICIs were observed between auranofin and amikacin (0.45) and linezolid (0.50). Auranofin exhibited concentration-dependent killing of M. abscessus, with >1-log killing at concentrations of >2x MIC. Only amikacin was synergistic with auranofin according to Bliss independence. Auranofin could not lower the intracellular bacterial load in macrophages. Auranofin itself may not be feasible for M. abscessus treatment, but these data point toward a promising, unutilized drug target.

引用

页数：11