Centre for Bacterial Cell Biology, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Richardson Road, Newcastle upon Tyne, NE2 4AX, UK.
Faculty of Medicine and Health, University of Sydney, Sydney, NSW, 2006, Australia.
Nat Commun. 2023 Jul 11;14(1):4123. doi: 10.1038/s41467-023-39723-8.
Inhibition of bacterial cell wall synthesis by antibiotics such as β-lactams is thought to cause explosive lysis through loss of cell wall integrity. However, recent studies on a wide range of bacteria have suggested that these antibiotics also perturb central carbon metabolism, contributing to death via oxidative damage. Here, we genetically dissect this connection in Bacillus subtilis perturbed for cell wall synthesis, and identify key enzymatic steps in upstream and downstream pathways that stimulate the generation of reactive oxygen species through cellular respiration. Our results also reveal the critical role of iron homeostasis for the oxidative damage-mediated lethal effects. We show that protection of cells from oxygen radicals via a recently discovered siderophore-like compound uncouples changes in cell morphology normally associated with cell death, from lysis as usually judged by a phase pale microscopic appearance. Phase paling appears to be closely associated with lipid peroxidation.
抗生素（如β-内酰胺类抗生素）抑制细菌细胞壁的合成，被认为会导致细胞壁完整性丧失而发生爆发性裂解。然而，最近对多种细菌的研究表明，这些抗生素还会扰乱中心碳代谢，通过氧化损伤导致死亡。在这里，我们在细胞壁合成受到干扰的枯草芽孢杆菌中对这种联系进行了遗传剖析，并确定了在上游和下游途径中刺激细胞呼吸产生活性氧的关键酶促步骤。我们的研究结果还揭示了铁稳态对氧化损伤介导的致死效应的关键作用。我们发现，通过最近发现的一种类似铁载体的化合物来保护细胞免受氧自由基的侵害，可以将通常与细胞死亡相关的细胞形态变化与通常通过相淡显微镜外观判断的裂解分开。相淡似乎与脂质过氧化密切相关。
