Abstract
Mycobacterium abscessus is a rapidly growing life-threatening mycobacterium with multiple drug-resistance mechanisms. However, there is no official regimen for M. abscessus therapy. In this study, we screened the Pathogen Box, which contains 400 drug-like molecules active against neglected diseases, to identify active molecules targeting Mycobacterium abscessus using resazurin live/dead assays. In this screening assay, the Z-factor was 0.7, as an indicator of the statistical confidence of the assay. A cut-off of 80% growth inhibition in the screening resulted in the identification of four different compounds at a single concentration (20 μM). Dose-response curves identified three different hit candidates, i.e., MMV688508, MMV688844, and MMV688845, which generated good inhibitory curves. All hit candidates were expected to have different molecular targets. Among them, MMV688844 showed the best minimum inhibitory concentration value for not only wild-type M. abscessus but also for nine different R and S morphotype clinical isolates. Thus, we found that MMV688844, identified from the Pathogen Box screen, may be a promising candidate in the M. abscessus drug discovery pipeline.
Highlights
Mycobacterium abscessus is a potentially life-threatening, pathogenic, rapidly growing mycobacterium (RGM) with multiple intrinsic and extrinsic drug-resistance mechanisms [1]
We found that MMV688844 was the best candidate with potential for lead optimization, exhibiting the lowest minimum inhibitory concentration (MIC) and strong activity against clinical isolates
We identified effective compounds using a screening assay with M. abscessus grown in the mid-log phase
Summary
Mycobacterium abscessus is a potentially life-threatening, pathogenic, rapidly growing mycobacterium (RGM) with multiple intrinsic and extrinsic drug-resistance mechanisms [1]. We screened the Pathogen Box, which contains 400 diverse, drug-like molecules active against neglected diseases, such as ascariasis, Buruli ulcer, Chagas disease, and malaria, in order to identify hit compounds for M. abscessus. We found that MMV688844 was the best candidate with potential for lead optimization, exhibiting the lowest minimum inhibitory concentration (MIC) and strong activity against clinical isolates. The MICs of the hit compounds were determined using twofold serial dilution assays.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
