Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Proc Natl Acad Sci U S A. 2013 May 14;110(20):8206-11. doi: 10.1073/pnas.1303674110. Epub 2013 Apr 29.
Staphylococcus aureus is a significant infectious threat to global public health. Acquisition or synthesis of heme is required for S. aureus to capture energy through respiration, but an excess of this critical cofactor is toxic to bacteria. S. aureus employs the heme sensor system (HssRS) to overcome heme toxicity; however, the mechanism of heme sensing is not defined. Here, we describe the identification of a small molecule activator of HssRS that induces endogenous heme biosynthesis by perturbing central metabolism. This molecule is toxic to fermenting S. aureus, including clinically relevant small colony variants. The utility of targeting fermenting bacteria is exemplified by the fact that this compound prevents the emergence of antibiotic resistance, enhances phagocyte killing, and reduces S. aureus pathogenesis. Not only is this small molecule a powerful tool for studying bacterial heme biosynthesis and central metabolism; it also establishes targeting of fermentation as a viable antibacterial strategy.
金黄色葡萄球菌是对全球公共健康的重大感染威胁。金黄色葡萄球菌通过呼吸获取能量需要获得或合成血红素，但这种关键辅因子的过量对细菌是有毒的。金黄色葡萄球菌利用血红素感应系统（HssRS）来克服血红素毒性；然而，血红素感应的机制尚未确定。在这里，我们描述了一种小分子 HssRS 激活剂的鉴定，该激活剂通过扰乱中心代谢来诱导内源性血红素生物合成。这种分子对发酵的金黄色葡萄球菌有毒，包括临床上相关的小菌落变种。该化合物能够防止抗生素耐药性的出现、增强吞噬细胞的杀伤作用并降低金黄色葡萄球菌的发病机制，这证明了靶向发酵细菌的实用性。这种小分子不仅是研究细菌血红素生物合成和中心代谢的有力工具；它还确立了靶向发酵作为一种可行的抗菌策略。
