Pi Hualiang, Burroughs Owen S, Carlin Sophia M, Beavers William N, Hillebrand Gideon H, Krystofiak Evan S, Stauff Devin L, Skaar Eric P
Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University, Nashville, Tennessee, USA.
Department of Pathology, Microbiology, & Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
mBio. 2025 Jun 11;16(6):e0205724. doi: 10.1128/mbio.02057-24. Epub 2025 May 23.
a Gram-positive facultative anaerobe and the causative agent of anthrax, multiplies to extraordinarily high numbers in vertebrate blood, resulting in considerable heme exposure. Heme is an essential nutrient and the preferred iron source for bacteria during vertebrate colonization, but its high redox potential makes it toxic in excess. To regulate heme homeostasis, many Gram-positive bacteria, including , rely on the two-component signaling system HssRS. HssRS comprises the heme sensing histidine kinase HssS, which modulates the activity of the HssR transcription factor to enable bacteria to circumvent heme toxicity. However, the regulation of the HssRS system remains unclear. Here, we identify FapR, the transcriptional regulator of fatty acid biosynthesis, as a key factor in HssRS function. FapR plays an important role in maintaining membrane integrity and the localization of the histidine kinase HssS. Specifically, disruption of leads to increased membrane rigidity, which hinders the penetration of HssRS inducers, resulting in the inactivation of HssRS. Furthermore, deletion of affects the loading of HssS onto the cell membrane, compromising its heme sensing function and subsequently reducing endogenous heme biosynthesis. These findings shed light on the molecular mechanisms governing bacterial adaptation to heme stress and provide potential targets for antimicrobial intervention strategies.
Understanding the mechanisms by which regulates heme homeostasis is crucial for developing new strategies to combat anthrax, a serious disease affecting both humans and animals. This study uncovers the role of the transcriptional regulator FapR in maintaining membrane integrity and facilitating the proper function of the HssRS two-component signaling system, which is essential for managing heme toxicity in , as well as other Gram-positive pathogens. By elucidating the connection between FapR and HssRS, our findings provide new insights into the molecular adaptation of bacteria to heme stress and expand our knowledge of bacterial physiology and pathogenicity. More importantly, targeting the regulatory pathways involved in heme sensing and homeostasis presents a promising approach for developing novel therapeutics against anthrax and potentially other bacterial infections that rely on similar mechanisms.
作为一种革兰氏阳性兼性厌氧菌以及炭疽病的病原体，在脊椎动物血液中大量繁殖，导致大量血红素暴露。血红素是一种必需营养素，也是细菌在脊椎动物定殖过程中首选的铁源，但其高氧化还原电位使其过量时具有毒性。为了调节血红素稳态，许多革兰氏阳性细菌，包括[具体细菌名称未给出]，依赖双组分信号系统HssRS。HssRS由血红素感应组氨酸激酶HssS组成，它调节HssR转录因子的活性，使细菌能够规避血红素毒性。然而，HssRS系统的调节机制仍不清楚。在这里，我们确定脂肪酸生物合成的转录调节因子FapR是HssRS功能的关键因素。FapR在维持膜完整性和组氨酸激酶HssS的定位中起重要作用。具体而言，[细菌名称未给出]的破坏导致膜刚性增加，这阻碍了HssRS诱导剂的渗透，导致HssRS失活。此外，[细菌名称未给出]的缺失影响HssS在细胞膜上的加载，损害其血红素感应功能，随后减少内源性血红素生物合成。这些发现揭示了细菌适应血红素应激的分子机制，并为抗菌干预策略提供了潜在靶点。
了解[细菌名称未给出]调节血红素稳态的机制对于开发对抗炭疽病的新策略至关重要，炭疽病是一种影响人类和动物的严重疾病。本研究揭示了转录调节因子FapR在维持膜完整性和促进HssRS双组分信号系统正常功能方面的作用，这对于管理[细菌名称未给出]以及其他革兰氏阳性病原体中的血红素毒性至关重要。通过阐明FapR与HssRS之间的联系，我们的发现为细菌对血红素应激的分子适应提供了新见解，并扩展了我们对细菌生理学和致病性的认识。更重要的是，针对参与血红素感应和稳态的调节途径是开发针对炭疽病以及可能依赖类似机制的其他细菌感染的新型疗法的有前景的方法。
