Tomas N Gustafsson1, Harer Osman2, Jim Werngren3, Sven Hoffner3, Lars Engman4, Arne Holmgren5. 1. Department of Medical Biochemistry and Biophysics, Division of Biochemistry, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Microbiology, Clinical Bacteriology, Sunderby Research Unit, Umeå University, Umeå, Sweden. Electronic address: tomas.gustafsson@umu.se. 2. Department of Medical Biochemistry and Biophysics, Division of Biochemistry, Karolinska Institutet, Stockholm, Sweden. 3. Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden. 4. Department of Chemistry, BMC, Uppsala University, Uppsala, Sweden. 5. Department of Medical Biochemistry and Biophysics, Division of Biochemistry, Karolinska Institutet, Stockholm, Sweden. Electronic address: arne.holmgren@ki.se.
Abstract
BACKGROUND: Bacillus anthracis is the causative agent of anthrax, a disease associated with a very high mortality rate in its invasive forms. METHODS: We studied a number of ebselen analogs as inhibitors of B. anthracis thioredoxin reductase and their antibacterial activity on Bacillus subtilis, Staphylococcus aureus, Bacillus cereus and Mycobacterium tuberculosis. RESULTS: The most potent compounds in the series gave IC(50) values down to 70 nM for the pure enzyme and minimal inhibitory concentrations (MICs) down to 0.4 μM (0.12 μg/ml) for B. subtilis, 1.5 μM (0.64 μg/ml) for S. aureus, 2 μM (0.86 μg/ml) for B. cereus and 10 μg/ml for M. tuberculosis. Minimal bactericidal concentrations (MBCs) were found at 1-1.5 times the MIC, indicating a general, class-dependent, bactericidal mode of action. The combined bacteriological and enzymological data were used to construct a preliminary structure-activity-relationship for the benzoisoselenazol class of compounds. When S. aureus and B. subtilis were exposed to ebselen, we were unable to isolate resistant mutants on both solid and in liquid medium suggesting a high resistance barrier. CONCLUSIONS: These results suggest that ebselen and analogs thereof could be developed into a novel antibiotic class, useful for the treatment of infections caused by B. anthracis, S. aureus, M. tuberculosis and other clinically important bacteria. Furthermore, the high barrier against resistance development is encouraging for further drug development. GENERAL SIGNIFICANCE: We have characterized the thioredoxin system from B. anthracis as a novel drug target and ebselen and analogs thereof as a potential new class of antibiotics targeting several important human pathogens.
BACKGROUND:Bacillus anthracis is the causative agent of anthrax, a disease associated with a very high mortality rate in its invasive forms. METHODS: We studied a number of ebselen analogs as inhibitors of B. anthracis thioredoxin reductase and their antibacterial activity on Bacillus subtilis, Staphylococcus aureus, Bacillus cereus and Mycobacterium tuberculosis. RESULTS: The most potent compounds in the series gave IC(50) values down to 70 nM for the pure enzyme and minimal inhibitory concentrations (MICs) down to 0.4 μM (0.12 μg/ml) for B. subtilis, 1.5 μM (0.64 μg/ml) for S. aureus, 2 μM (0.86 μg/ml) for B. cereus and 10 μg/ml for M. tuberculosis. Minimal bactericidal concentrations (MBCs) were found at 1-1.5 times the MIC, indicating a general, class-dependent, bactericidal mode of action. The combined bacteriological and enzymological data were used to construct a preliminary structure-activity-relationship for the benzoisoselenazol class of compounds. When S. aureus and B. subtilis were exposed to ebselen, we were unable to isolate resistant mutants on both solid and in liquid medium suggesting a high resistance barrier. CONCLUSIONS: These results suggest that ebselen and analogs thereof could be developed into a novel antibiotic class, useful for the treatment of infections caused by B. anthracis, S. aureus, M. tuberculosis and other clinically important bacteria. Furthermore, the high barrier against resistance development is encouraging for further drug development. GENERAL SIGNIFICANCE: We have characterized the thioredoxin system from B. anthracis as a novel drug target and ebselen and analogs thereof as a potential new class of antibiotics targeting several important human pathogens.
Authors: Lili Zou; Jun Lu; Jun Wang; Xiaoyuan Ren; Lanlan Zhang; Yu Gao; Martin E Rottenberg; Arne Holmgren Journal: EMBO Mol Med Date: 2017-08 Impact factor: 12.137
Authors: Noreena L Sweeney; Lauren Lipker; Alicia M Hanson; Chris J Bohl; Katie E Engel; Kelsey S Kalous; Mary E Stemper; Daniel S Sem; William R Schwan Journal: Antibiotics (Basel) Date: 2017-01-28
Authors: Karolina Witek; Muhammad Jawad Nasim; Markus Bischoff; Rosmarie Gaupp; Pavel Arsenyan; Jelena Vasiljeva; Małgorzata Anna Marć; Agnieszka Olejarz; Gniewomir Latacz; Katarzyna Kieć-Kononowicz; Jadwiga Handzlik; Claus Jacob Journal: Molecules Date: 2017-12-08 Impact factor: 4.411
Authors: Gina Wall; Ashok K Chaturvedi; Floyd L Wormley; Nathan P Wiederhold; Hoja P Patterson; Thomas F Patterson; José L Lopez-Ribot Journal: Antimicrob Agents Chemother Date: 2018-09-24 Impact factor: 5.191
Authors: Holly C May; Jieh-Juen Yu; M N Guentzel; James P Chambers; Andrew P Cap; Bernard P Arulanandam Journal: Front Microbiol Date: 2018-03-05 Impact factor: 5.640