Extracellular Matrix Rigidities Regulate the Tricarboxylic Acid Cycle and Antibiotic Resistance of Three‐Dimensionally Confined Bacterial Microcolonies. Issue 9 (19th January 2023)

• Record Type: Journal Article
• Authors: Han, Yiming; Jiang, Nan; Xu, Hongwei; Yuan, Zuoying; Xiu, Jidong; Mao, Sheng; Liu, Xiaozhi; Huang, Jianyong
• Is Part Of: Advanced science. Volume 10:Issue 9(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-01-19
• Subjects: bacterial biofilm -- matrix stiffness -- mechanobiology -- metabolism -- minimum biofilm elimination concentration; Science -- Periodicals; 505
• DOI: 10.1002/advs.202206153
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: As a major cause of clinical chronic infection, microbial biofilms/microcolonies in host tissues essentially live in 3D‐constrained microenvironments, which potentially modulate their spatial self‐organization and morphodynamics. However, it still remains unclear whether and how mechanical cues of 3D confined microenvironments, for example, extracellular matrix (ECM) stiffness, exert an impact on antibiotic resistance of bacterial biofilms/microcolonies. With a high‐throughput antibiotic sensitivity testing (AST) platform, it is revealed that 3D ECM rigidities greatly modulate their resistance to diverse antibiotics. The microcolonies in 3D ECM with human tissue‐specific rigidities varying from 0.5 to 20 kPa show a ≈2–10 000‐fold increase in minimum inhibitory concentration, depending on the types of antibiotics. The authors subsequently identified that the increase in 3D ECM rigidities leads to the downregulation of the tricarboxylic acid (TCA) cycle, which is responsible for enhanced antibiotic resistance. Further, it is shown that fumarate, as a potentiator of TCA cycle activity, can alleviate the elevated antibiotic resistance and thus remarkably improve the efficacy of antibiotics against bacterial microcolonies in 3D confined ECM, as confirmed in the chronic infection mice model. These findings suggest fumarate can be employed as an antibiotic adjuvant to effectively treat infections induced by bacterial biofilms/microcolonies in a 3D‐confined environment. Abstract : It remains elusive whether and how mechanical cures regulate antibiotic resistance of bacterial biofilms/microcolonies in 3D confined microenvironments. With a high‐throughput antibiotic sensitivity testing platform, this study not only reveals that 3D extracellular matrix rigidities enhance antibiotics resistance of microcolonies via the tricarboxylic acid cycle, but recognizes that fumarate can be used as an antibiotic adjuvant to treat infections.