Identification of Small Molecule Inhibitors of the Pathogen Box against Vibrio cholerae
ABSTRACT Antimicrobial resistance (AMR) has become a serious public and economic threat. The rate of bacteria acquiring AMR surpasses the rate of new antibiotics discovery, projecting more deadly AMR infections in the future. The Pathogen Box is an open-source library of drug-like compounds that can...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2021-12-01
|
| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/Spectrum.00739-21 |
| _version_ | 1798015812075782144 |
|---|---|
| author | Haeun Kim Brianne J. Burkinshaw Linh G. Lam Kevin Manera Tao G. Dong |
| author_facet | Haeun Kim Brianne J. Burkinshaw Linh G. Lam Kevin Manera Tao G. Dong |
| author_sort | Haeun Kim |
| collection | DOAJ |
| description | ABSTRACT Antimicrobial resistance (AMR) has become a serious public and economic threat. The rate of bacteria acquiring AMR surpasses the rate of new antibiotics discovery, projecting more deadly AMR infections in the future. The Pathogen Box is an open-source library of drug-like compounds that can be screened for antibiotic activity. We have screened molecules of the Pathogen Box against Vibrio cholerae, the cholera-causing pathogen, and successfully identified two compounds, MMV687807 and MMV675968, that inhibit growth. RNA-seq analyses of V. cholerae after incubation with each compound revealed that both compounds affect cellular functions on multiple levels including carbon metabolism, iron homeostasis, and biofilm formation. In addition, whole-genome sequencing analysis of spontaneous resistance mutants identified an efflux system that confers resistance to MMV687807. We also identified that the dihydrofolate reductase is the likely target of MMV675968 suggesting it acts as an analog of trimethoprim but with a MIC 14-fold lower than trimethoprim in molar concentration. In summary, these two compounds that effectively inhibit V. cholerae and other bacteria may lead to the development of new antibiotics for better treatment of the cholera disease. IMPORTANCE Cholera is a serious infectious disease in tropical regions causing millions of infections annually. Vibrio cholerae, the causative agent of cholera, has gained multi-antibiotic resistance over the years, posing greater threat to public health and current treatment strategies. Here we report two compounds that effectively target the growth of V. cholerae and have the potential to control cholera infection. |
| first_indexed | 2024-04-11T15:40:44Z |
| format | Article |
| id | doaj.art-c660b948f543459d970eb5036b75fc47 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-04-11T15:40:44Z |
| publishDate | 2021-12-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-c660b948f543459d970eb5036b75fc472022-12-22T04:15:50ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972021-12-019310.1128/Spectrum.00739-21Identification of Small Molecule Inhibitors of the Pathogen Box against Vibrio choleraeHaeun Kim0Brianne J. Burkinshaw1Linh G. Lam2Kevin Manera3Tao G. Dong4Department of Ecosystem and Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, CanadaDepartment of Ecosystem and Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, CanadaDepartment of Ecosystem and Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, CanadaDepartment of Ecosystem and Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, CanadaDepartment of Ecosystem and Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, CanadaABSTRACT Antimicrobial resistance (AMR) has become a serious public and economic threat. The rate of bacteria acquiring AMR surpasses the rate of new antibiotics discovery, projecting more deadly AMR infections in the future. The Pathogen Box is an open-source library of drug-like compounds that can be screened for antibiotic activity. We have screened molecules of the Pathogen Box against Vibrio cholerae, the cholera-causing pathogen, and successfully identified two compounds, MMV687807 and MMV675968, that inhibit growth. RNA-seq analyses of V. cholerae after incubation with each compound revealed that both compounds affect cellular functions on multiple levels including carbon metabolism, iron homeostasis, and biofilm formation. In addition, whole-genome sequencing analysis of spontaneous resistance mutants identified an efflux system that confers resistance to MMV687807. We also identified that the dihydrofolate reductase is the likely target of MMV675968 suggesting it acts as an analog of trimethoprim but with a MIC 14-fold lower than trimethoprim in molar concentration. In summary, these two compounds that effectively inhibit V. cholerae and other bacteria may lead to the development of new antibiotics for better treatment of the cholera disease. IMPORTANCE Cholera is a serious infectious disease in tropical regions causing millions of infections annually. Vibrio cholerae, the causative agent of cholera, has gained multi-antibiotic resistance over the years, posing greater threat to public health and current treatment strategies. Here we report two compounds that effectively target the growth of V. cholerae and have the potential to control cholera infection.https://journals.asm.org/doi/10.1128/Spectrum.00739-21antibioticsPathogen BoxcholeraAMRsmall molecule |
| spellingShingle | Haeun Kim Brianne J. Burkinshaw Linh G. Lam Kevin Manera Tao G. Dong Identification of Small Molecule Inhibitors of the Pathogen Box against Vibrio cholerae Microbiology Spectrum antibiotics Pathogen Box cholera AMR small molecule |
| title | Identification of Small Molecule Inhibitors of the Pathogen Box against Vibrio cholerae |
| title_full | Identification of Small Molecule Inhibitors of the Pathogen Box against Vibrio cholerae |
| title_fullStr | Identification of Small Molecule Inhibitors of the Pathogen Box against Vibrio cholerae |
| title_full_unstemmed | Identification of Small Molecule Inhibitors of the Pathogen Box against Vibrio cholerae |
| title_short | Identification of Small Molecule Inhibitors of the Pathogen Box against Vibrio cholerae |
| title_sort | identification of small molecule inhibitors of the pathogen box against vibrio cholerae |
| topic | antibiotics Pathogen Box cholera AMR small molecule |
| url | https://journals.asm.org/doi/10.1128/Spectrum.00739-21 |
| work_keys_str_mv | AT haeunkim identificationofsmallmoleculeinhibitorsofthepathogenboxagainstvibriocholerae AT briannejburkinshaw identificationofsmallmoleculeinhibitorsofthepathogenboxagainstvibriocholerae AT linhglam identificationofsmallmoleculeinhibitorsofthepathogenboxagainstvibriocholerae AT kevinmanera identificationofsmallmoleculeinhibitorsofthepathogenboxagainstvibriocholerae AT taogdong identificationofsmallmoleculeinhibitorsofthepathogenboxagainstvibriocholerae |