β-Lactam–resistant (BLR) Gram-negative bacteria that are difficult or impossible to treat are causing a global health threat. However, the development of effective nanoantibiotics is limited by the poor understanding of changes in the physical nature of BLR Gram-negative bacteria. Here, we systematically explored the nanomechanical properties of a range of Gram-negative bacteria (Salmonella, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae) with different degrees of β-lactam resistance. Our observations indicated that the BLR bacteria had cell stiffness values almost 10× lower than that of β-lactam–susceptible bacteria, caused by reduced peptidoglycan biosynthesis. With the aid of numerical modeling and experimental measurements, we demonstrated that these stiffness findings can be used to develop programmable, stiffness-mediated antimicrobial nanowires that mechanically penetrate the BLR bacterial cell envelope. We anticipate that these stiffness-related findings will aid in the discovery and development of novel treatment strategies for BLR Gram-negative bacterial infections.

难以或不可能治疗的 β-内酰胺耐药 (BLR) 革兰氏阴性菌正在对全球健康造成威胁。然而，有效纳米抗生素的开发受到对 BLR 革兰氏阴性细菌物理性质变化的了解不足的限制。在这里，我们系统地探索了一系列革兰氏阴性菌（沙门氏菌、大肠杆菌、铜绿假单胞菌和肺炎克雷伯菌）的纳米力学特性。) 具有不同程度的 β-内酰胺抗性。我们的观察表明，由于肽聚糖生物合成减少，BLR 细菌的细胞刚度值几乎比 β-内酰胺敏感细菌低 10 倍。在数值建模和实验测量的帮助下，我们证明了这些刚度发现可用于开发可编程的、刚度介导的抗菌纳米线，该纳米线机械地穿透 BLR 细菌细胞包膜。我们预计这些与硬度相关的发现将有助于发现和开发 BLR 革兰氏阴性细菌感染的新治疗策略。