Imbalance between cell biomass production and envelope biosynthesis underpins the bactericidal activity of cell wall -targeting antibiotics

我们临床上最成功的大多数抗生素针对的细胞过程令人惊讶地少。突出的一线抗生素类青霉素和头孢菌素，也是用于治疗危及生命的多重耐药感染的最后手段抗生素万古霉素和达托霉素，瞄准细菌细胞壁合成机制。尽管进行了广泛的研究，但细胞壁靶向抗生素是如何杀死细菌的，以及为什么它们在临床上如此成功，仍然是个谜。教科书上对细胞壁靶向抗生素杀菌活性的解释是诱导细胞溶解。然而，这忽略了这样一个事实，即细菌死亡的速度可能快于它们的裂解速度，而且裂解往往不是有效杀灭所必需的。最近，我们有了一个惊人的发现，壁靶向抗生素会引发一系列独立于诱导的细胞裂解过程的细胞紊乱。因此，为了了解这类重要的抗生素是如何发挥其抗菌性能的，现在需要详细研究导致裂解非依赖性杀伤的细胞过程。研究已知抗生素的这种过程对于真正了解广泛使用的抗生素类别是如何发挥作用很重要，也是为了破译为什么它们具有相对较低的抗菌素耐药性(AMR)发展率，这是它们临床成功的关键。至关重要的是，研究这些过程将使我们能够指导下一代新抗生素的开发，以达到本质上较低的耐药性发展风险的细胞靶点。在Henrik Strahl(纽卡斯尔大学生物科学研究所细菌细胞生物学中心)和Rebecca Corrigan(谢菲尔德大学生物科学学院)团队之间的这个密切合作项目中，将在革兰氏阴性模型生物大肠杆菌中分析新发现的细胞靶向抗生素的作用模式。该研究方案广泛使用先进的显微技术，如微流控设备、超分辨率显微镜和高速成像，结合细菌遗传学、生长动力学、抗生素耐药性和压力分析。

The majority of our clinically most successful antibiotics target surprisingly few cellular processes. The prominent first-line antibiotic-classes penicillins and cephalosporins, but also the last resort antibiotics vancomycin and daptomycin that are used to treat life-threatening multidrug resistant infections, target the bacterial cell wall synthesis machinery. Despite extensive research, how cell wall -targeting antibiotics kill bacteria and why they are clinically so exceptionally successful has remained enigmatic. The textbook explanation for the bactericidal activity of cell wall -targeting antibiotic is induced cell lysis. However, this ignores the fact that bacteria can die faster than they lyse, and that lysis is frequently not required for efficient killing. Recently, we made the striking discovery that wall-targeting antibiotics trigger a cascade of cellular disturbances that are independent of the induced cell lysis process. Hence, to understand how this prominent class of antibiotics unfolds its antibacterial properties, the cellular processes leading to the lysis-independent killing now needs to be studied in detail. Studying such processes for known antibiotics is important to truly understand how widely used antibiotic classes work, but also to decipher why they share a comparatively low rate of antimicrobial resistance (AMR) development, a property that is key for their clinically success. Crucially, studying these processes will allow us to guide the development of the next generation of new antibiotics towards cellular targets with intrinsically lower risk of resistance development. In this closely collaborative project between the groups of Henrik Strahl (Centre for Bacterial Cell Biology, Biosciences Institute, Newcastle University) and Rebecca Corrigan (School of Biosciences, University of Sheffield), the newly discovered mode of action of cell targeting antibiotics will be analysed in the Gram-negative model organism Escherichia coli. The research programme makes extensive use of advanced microscopy techniques such as microfluidic devises, super resolution microscopy and high-speed imaging, combined with bacterial genetics, growth dynamics, and antibiotic resistance and stress profiling.