Canchola Juan, Donkor Gracious Yoofi Boafo, Tawiah Patrick Ofori, Fasawe Ayoola, Ayim Emmanuel, Engelke Martin F, Dahl Jan-Ulrik
Department of Chemistry, Illinois State University, Normal, IL 61761, USA.
School of Biological Sciences, Microbiology, Illinois State University, Normal, IL 61761, USA.
Antibiotics (Basel). 2024 Sep 20;13(9):897. doi: 10.3390/antibiotics13090897.
The rise of antibiotic-resistant pathogens represents a significant global challenge in infectious disease control, which is amplified by the decline in the discovery of novel antibiotics. continues to be a highly significant pathogen, causing infections in multiple organs and tissues in both healthcare institutions and community settings. The bacterium has become increasingly resistant to all available antibiotics. Consequently, there is an urgent need for novel small molecules that inhibit the growth or impair the survival of bacterial pathogens. Given their large structural and chemical diversity, as well as often unique mechanisms of action, natural products represent an excellent avenue for the discovery and development of novel antimicrobial treatments. Anaephene A and B are two such naturally occurring compounds with significant antimicrobial activity against Gram-positive bacteria. Here, we report the rapid syntheses and biological characterization of five novel anaephene derivatives, which display low cytotoxicity against mammalian cells but potent antibacterial activity against various strains, including methicillin-resistant (MRSA) and the multi-drug-resistant community-acquired strain USA300LAC. A Sonogashira cross-coupling reaction served as the key step for the synthesis of the alkyl pyridinol products. Using the compound JC-01-074, which displays bactericidal activity already at low concentrations (MIC: 16 μg/mL), we provide evidence that alkyl pyridinols target actively growing and biofilm-forming cells and show that these compounds cause disruption and deformation of the staphylococcal membrane, indicating a membrane-associated mechanism of action.
抗生素耐药性病原体的出现是传染病控制领域一项重大的全球挑战，新型抗生素发现数量的减少更是加剧了这一挑战。[病原体名称]仍然是一种极具威胁的病原体，在医疗机构和社区环境中均可导致多个器官和组织发生感染。该细菌对所有现有抗生素的耐药性日益增强。因此，迫切需要能够抑制细菌性病原体生长或损害其生存能力的新型小分子。鉴于天然产物具有巨大的结构和化学多样性，以及通常独特的作用机制，它们是发现和开发新型抗菌疗法的绝佳途径。Anaephene A和B就是两种对革兰氏阳性菌具有显著抗菌活性的天然化合物。在此，我们报告了五种新型anaephene衍生物的快速合成及生物学特性，这些衍生物对哺乳动物细胞显示出低细胞毒性，但对包括耐甲氧西林金黄色葡萄球菌（MRSA）和多药耐药社区获得性菌株USA300LAC在内的多种菌株具有强效抗菌活性。Sonogashira交叉偶联反应是合成烷基吡啶醇产物的关键步骤。使用在低浓度（MIC：16 μg/mL）时即具有杀菌活性的化合物JC-01-074，我们证明烷基吡啶醇靶向活跃生长和形成生物膜的细胞，并表明这些化合物会导致葡萄球菌膜的破坏和变形，这表明其作用机制与膜相关。
