The emergence of multidrug-resistant Staphylococcus aureus strains has become a serious clinical problem. Iron is absolutely required for the bacterial growth, virulence associated with colonization, and survival from the host immune system. The FeoB protein is a major iron permease in bacterial ferrous iron transport systems (Feo) that has been shown to play a crucial role in virulence of some pathogenic bacteria. However, FeoB is still uncharacterized in Gram-positive pathogens, and its effects on S. aureus pathogenesis are unknown. In this study, we identified a novel inhibitor, GW3965·HCl, that targets FeoB in S. aureus. The molecule effectively inhibited FeoB in vitro enzyme activity, bacterial growth, and virulence factor expression. Genome-editing and metabolomic analyses revealed that GW3965·HCl inhibited FeoB function and affected the associated mechanisms with reduced iron availability in S. aureus. Gentamicin resistance and Caenorhabditis elegans infection assays further demonstrated the power of GW3965·HCl as a safe and efficient antibacterial agent. In addition to S. aureus, GW3965·HCl also presented its effectiveness on inhibition of the FeoB activity and growth of Gram-positive bacteria. This novel inhibitor will provide new insight for developing a next-generation antibacterial therapy.

中文翻译：

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针对金黄色葡萄球菌和革兰氏阳性细菌的靶向铁转运蛋白FeoB的抗菌剂的表征

多药耐药金黄色葡萄球菌菌株的出现已成为严重的临床问题。铁是细菌生长，与定殖有关的毒力以及宿主免疫系统生存所必需的铁。FeoB蛋白是细菌亚铁转运系统（Feo）中的主要铁渗透酶，已显示在某些致病细菌的毒力中起关键作用。然而，FeoB在革兰氏阳性病原体中仍未表征，其对金黄色葡萄球菌发病机理的影响尚不清楚。在这项研究中，我们确定了针对金黄色葡萄球菌FeoB的新型抑制剂GW3965·HCl 。该分子在体外有效抑制FeoB酶活性，细菌生长和毒力因子表达。基因组编辑和代谢组学分析表明，GW3965·HCl抑制FeoB功能并影响相关机制，导致金黄色葡萄球菌铁利用率降低。庆大霉素抗性和秀丽隐杆线虫感染的测定进一步证明了GW3965·HCl作为安全有效的抗菌剂的功效。除金黄色葡萄球菌外，GW3965·HCl还显示出其对FeoB活性和革兰氏阳性细菌生长的抑制作用。这种新型抑制剂将为开发下一代抗菌疗法提供新的见解。