期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：47
DOI：10.1073/pnas.2108244118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Considering the alarming emergence of resistance to most antibiotics and the need for new antibiotics, the finding here of a small-molecule class, THCz, that displayed bactericidal activity against gram-positive and selected gram-negative bacteria, is of the greatest importance. We found that THCz target the cell envelope synthesis and can easily be synthesized and modified, and resistance did not readily develop in vitro. Thus, THCz are promising scaffolds for development of bacterial cell wall inhibitors.
Emerging antibiotic resistance demands identification of novel antibacterial compound classes. A bacterial whole-cell screen based on pneumococcal autolysin-mediated lysis induction was developed to identify potential bacterial cell wall synthesis inhibitors. A hit class comprising a 1-amino substituted tetrahydrocarbazole (THCz) scaffold, containing two essential amine groups, displayed bactericidal activity against a broad range of gram-positive and selected gram-negative pathogens in the low micromolar range. Mode of action studies revealed that THCz inhibit cell envelope synthesis by targeting undecaprenyl pyrophosphate–containing lipid intermediates and thus simultaneously inhibit peptidoglycan, teichoic acid, and polysaccharide capsule biosynthesis. Resistance did not readily develop in vitro, and the ease of synthesizing and modifying these small molecules, as compared to natural lipid II–binding antibiotics, makes THCz promising scaffolds for development of cell wall–targeting antimicrobials.
