Roman-Rodriguez Franklin, Kim Jisun, Parker Dane, Boyd Jeffrey M
Department of Biochemistry and Microbiology, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.
Department of Pathology, Immunology and Laboratory Medicine, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
bioRxiv. 2025 Mar 12:2025.03.12.642861. doi: 10.1101/2025.03.12.642861.
and are primary bacterial pathogens isolated from the airways of cystic fibrosis patients. produces secondary metabolites that negatively impact the fitness of , allowing to become the most prominent bacterium when the species are co-cultured. Some of these metabolites inhibit respiration. SrrAB is a staphylococcal two-component regulatory system (TCRS) that responds to alterations in respiratory status and helps transition between fermentative and respiratory metabolisms. We used mutant strains and chemical genetics to demonstrate that secondary metabolites, HQNO in particular, inhibit respiration, resulting in modified SrrAB stimulation. Metabolomic analyses found that the ratio of NAD to NADH increased upon prolonged culture with HQNO. Consistent with this, the activity of the Rex transcriptional regulator, which senses and responds to alterations in the NAD / NADH ratio, had altered activity upon HQNO treatment. The presence of SrrAB increased fitness when cultured with HQNO and increased survival when challenged with strains with a decreased ability to maintain redox homeostasis via fermentation had decreased fitness when challenged with HQNO and decreased survival when challenged with . These findings led to a model wherein secreted HQNO inhibits respiration, stimulating SrrAB, which promotes fitness and survival by increasing carbon flux through fermentative pathways to maintain redox homeostasis.
[细菌名称1]和[细菌名称2]是从囊性纤维化患者气道中分离出的主要细菌病原体。[细菌名称1]产生的次级代谢产物会对[细菌名称2]的适应性产生负面影响，使得在共培养时[细菌名称2]成为最主要的细菌。其中一些代谢产物会抑制[细菌名称2]的呼吸作用。SrrAB是一种葡萄球菌双组分调节系统（TCRS），可对呼吸状态的变化做出反应，并帮助[细菌名称1]在发酵代谢和呼吸代谢之间转换。我们使用[细菌名称1]突变株和化学遗传学方法证明，[细菌名称1]的次级代谢产物，尤其是羟基萘醌（HQNO），会抑制[细菌名称2]的呼吸作用，导致SrrAB刺激发生改变。代谢组学分析发现，与HQNO长时间共培养后，NAD与NADH的比例增加。与此一致的是，感知并响应NAD/NADH比例变化的Rex转录调节因子的活性在HQNO处理后发生了改变。与HQNO一起培养时，SrrAB的存在提高了适应性，而当受到通过发酵维持氧化还原稳态能力降低的[细菌名称2]菌株攻击时，SrrAB的存在提高了存活率；受到HQNO攻击时，通过发酵维持氧化还原稳态能力降低的[细菌名称2]菌株适应性降低，受到[细菌名称1]攻击时存活率降低。这些发现导致了一个模型，即[细菌名称1]分泌的HQNO抑制[细菌名称2]的呼吸作用，刺激SrrAB，SrrAB通过增加发酵途径的碳通量来维持氧化还原稳态，从而促进适应性和存活。
