Department of Pediatric Dentistry, University of Alabama at Birmingham Schools of Dentistry and Medicine, Birmingham, Alabama, USA.
Department of Microbiology, University of Alabama at Birmingham Schools of Dentistry and Medicine, Birmingham, Alabama, USA.
mBio. 2023 Jun 27;14(3):e0013723. doi: 10.1128/mbio.00137-23. Epub 2023 Apr 19.
Antibiotic tolerance within a biofilm community presents a serious public health challenge. Here, we report the identification of a 2-aminoimidazole derivative that inhibits biofilm formation by two pathogenic Gram-positive bacteria, Streptococcus mutans and Staphylococcus aureus. In S. mutans, the compound binds to VicR, a key response regulator, at the N-terminal receiver domain, and concurrently inhibits expression of and VicR-regulated genes, including the genes that encode the key biofilm matrix producing enzymes, Gtfs. The compound inhibits S. aureus biofilm formation via binding to a Staphylococcal VicR homolog. In addition, the inhibitor effectively attenuates S. mutans virulence in a rat model of dental caries. As the compound targets bacterial biofilms and virulence through a conserved transcriptional factor, it represents a promising new class of anti-infective agents that can be explored to prevent or treat a host of bacterial infections. Antibiotic resistance is a major public health issue due to the growing lack of effective anti-infective therapeutics. New alternatives to treat and prevent biofilm-driven microbial infections, which exhibit high tolerance to clinically available antibiotics, are urgently needed. We report the identification of a small molecule that inhibits biofilm formation by two important pathogenic Gram-positive bacteria, Streptococcus mutans and Staphylococcus aureus. The small molecule selectively targets a transcriptional regulator leading to attenuation of a biofilm regulatory cascade and concurrent reduction of bacterial virulence . As the regulator is highly conserved, the finding has broad implication for the development of antivirulence therapeutics that selectively target biofilms.
生物膜内的抗生素耐药性是一个严重的公共卫生挑战。在这里，我们报告了一种 2-氨基咪唑衍生物的鉴定，该化合物能抑制两种致病性革兰氏阳性细菌——变形链球菌和金黄色葡萄球菌的生物膜形成。在变形链球菌中，该化合物结合到关键反应调节剂 VicR 的 N 端受体结构域，并同时抑制 VicR 调节基因的表达，包括编码关键生物膜基质产生酶 Gtfs 的基因。该化合物通过与葡萄球菌 VicR 同源物结合来抑制金黄色葡萄球菌生物膜的形成。此外，该抑制剂在龋齿大鼠模型中有效减弱了变形链球菌的毒力。由于该抑制剂通过保守的转录因子靶向细菌生物膜和毒力，因此它代表了一类有前途的新型抗感染药物，可用于预防或治疗多种细菌感染。抗生素耐药性是一个主要的公共卫生问题，因为现有的抗感染治疗方法越来越缺乏效果。急需新的替代方法来治疗和预防生物膜驱动的微生物感染，这些感染对临床可用的抗生素具有高度耐药性。我们报告了一种小分子的鉴定，该小分子能抑制两种重要的致病性革兰氏阳性细菌——变形链球菌和金黄色葡萄球菌的生物膜形成。这种小分子选择性地靶向一个转录调节剂，导致生物膜调节级联反应的衰减和细菌毒力的同时降低。由于调节剂高度保守，这一发现对开发选择性靶向生物膜的抗毒力治疗方法具有广泛的意义。
