Heat shock potentiates aminoglycosides against gram-negative bacteria by enhancing antibiotic uptake, protein aggregation, and ROS

Lv，Boyan1; Huang，Xuebing1; Lijia，Chenchen1; Ma，Yuelong1; Bian，Mengmeng1; Li，Zhongyan1; Duan，Juan2; Zhou，Fang3; Yang，Bin4; Qie，Xingwang5; Song，Yizhi5; Wood，Thomas K.6; Fu，Xinmiao1,7

2023-03-21

10.1073/pnas.2217254120

Proceedings of the National Academy of Sciences of the United States of America   影响因子和分区

0027-8424

1091-6490

The potentiation of antibiotics is a promising strategy for combatting antibiotic-resistant/tolerant bacteria. Herein, we report that a 5-min sublethal heat shock enhances the bactericidal actions of aminoglycoside antibiotics by six orders of magnitude against both exponential- and stationary-phase Escherichia coli. This combined treatment also effectively kills various E. coli persisters, E. coli clinical isolates, and numerous gram-negative but not gram-positive bacteria and enables aminoglycosides at 5% of minimum inhibitory concentrations to eradicate multidrug-resistant pathogens Acinetobacter baumannii and Klebsiella pneumoniae. Mechanistically, the potentiation is achieved comprehensively by heat shock-enhanced proton motive force that thus promotes the bacterial uptake of aminoglycosides, as well as by increasing irreversible protein aggregation and reactive oxygen species that further augment the downstream lethality of aminoglycosides. Consistently, protonophores, chemical chaperones, antioxidants, and anaerobic culturing abolish heat shock-enhanced aminoglycoside lethality. We also demonstrate as a proof of concept that infrared irradiation- or photothermal nanosphere-induced thermal treatments potentiate aminoglycoside killing of Pseudomonas aeruginosa in a mouse acute skin wound model. Our study advances the understanding of the mechanism of actions of aminoglycosides and demonstrates a high potential for thermal ablation in curing bacterial infections when combined with aminoglycosides.

antibiotic adjuvant antibiotic resistance bacterial persister photothermal therapeutic material reactive oxygen species

英语

NI论文

其他

Natural Science Foundation of Fujian Province[2021J02029];National Natural Science Foundation of China[31972918];

BIOLOGY & BIOCHEMISTRY;CLINICAL MEDICINE;MULTIDISCIPLINARY;PLANT & ANIMAL SCIENCE;ENVIRONMENT/ECOLOGY;SOCIAL SCIENCES, GENERAL;MICROBIOLOGY;ECONOMICS BUSINESS;IMMUNOLOGY;MATERIALS SCIENCE;MATHEMATICS;SPACE SCIENCE;MOLECULAR BIOLOGY & GENETICS;PHARMACOLOGY & TOXICOLOGY;CHEMISTRY;PSYCHIATRY/PSYCHOLOGY;NEUROSCIENCE & BEHAVIOR;PHYSICS;GEOSCIENCES;AGRICULTURAL SCIENCES;ENGINEERING

2-s2.0-85150294367

Scopus

1.Provincial University Key Laboratory of Cellular Stress Response and Metabolic Regulation,Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of Education,College of Life Sciences,Fujian Normal University,Fuzhou City,350117,China
2.Department of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Fujian Medical University,Fuzhou City,350122,China
3.Department of Pharmacy,Southern University of Science and Technology Hospital,Shenzhen City,518055,China
4.Department of Laboratory Medicine,The First Affiliated Hospital of Fujian Medical University,Fuzhou,350122,China
5.CAS Key Laboratory of BioMedical Diagnostics,Suzhou Institute of Biomedical Engineering and Technology,Chinese Academy of Sciences,Suzhou,215163,China
6.Department of Chemical Engineering,Pennsylvania State University,University Park,16802-4400,United States
7.Engineering Research Center of Industrial Microbiology of Ministry of Education,Fujian Normal University,Fuzhou City,350117,China

Lv，Boyan,Huang，Xuebing,Lijia，Chenchen,et al. Heat shock potentiates aminoglycosides against gram-negative bacteria by enhancing antibiotic uptake, protein aggregation, and ROS[J]. Proceedings of the National Academy of Sciences of the United States of America,2023,120(12).

Lv，Boyan.,Huang，Xuebing.,Lijia，Chenchen.,Ma，Yuelong.,Bian，Mengmeng.,...&Fu，Xinmiao.(2023).Heat shock potentiates aminoglycosides against gram-negative bacteria by enhancing antibiotic uptake, protein aggregation, and ROS.Proceedings of the National Academy of Sciences of the United States of America,120(12).

Lv，Boyan,et al."Heat shock potentiates aminoglycosides against gram-negative bacteria by enhancing antibiotic uptake, protein aggregation, and ROS".Proceedings of the National Academy of Sciences of the United States of America 120.12(2023).