PROFILING THE IN VITRO AND EX VIVO ANTIBACTERIAL ACTIVITIES OF TETRAZOLE-BASED TRANS-TRANSLATION INHIBITORS AGAINST BACILLUS ANTHRACIS
Drug-resistant pathogenic bacteria have become an increasing health hazard in the U.S. These bacteria present the need for exploration of alternative pathways that can be targeted for antibiotic development to surmount these multi-drug resistant pathogens. Bacillus anthracis, the causative agent of anthrax, has been classified as a bioterror agent because of its pathogenicity in vegetative form and its ability to thrive for decades as spores. These spores are resistant to extreme environmental stress and there are no current antibiotics that can kill them. There has been ongoing research to find a new pathway present in bacterial cells to serve as a potential antibacterial target. The quality control pathway exploited in this ongoing investigation is trans-translation. This process works by releasing stalled ribosomes, which have stopped translation due to a missing stop codon, and targeting the emerging polypeptides and mRNAs for degradation. Because so many bacteria thrive due to trans-translation, elimination of this pathway is damaging to bacterial cells. Compounds that inhibit trans-translation were identified through a high-throughput screen (HTS). These compounds were tested for antibiotic activity and, based on multiple assays, five of the compounds were selected for further analysis, including KKL-55. My research investigates the activity profile of KKL-2160 and KKL-2161, both of which are structural analogs of KKL-55 from the tetrazole family. These analogs were developed to improve the activity of KKL-55. Experimental techniques used explore the ability of these analogs to inhibit B. anthracis spore germination, kill spores, and assess potential cytotoxicity. Results thus far have proven these analogs to be 25-fold more active than their parent, KKL-55. Results also show that they inhibit spore germination, kill spores and protect RAW macrophages from anthrax toxin. These data together with their low cytotoxicity makes them good candidates for development as antibiotics for spore-related infections.
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|Work Title||PROFILING THE IN VITRO AND EX VIVO ANTIBACTERIAL ACTIVITIES OF TETRAZOLE-BASED TRANS-TRANSLATION INHIBITORS AGAINST BACILLUS ANTHRACIS|
|License||All rights reserved|
|Deposited||April 17, 2019|
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