L-glutamine sensitizes Gram-positive-resistant bacteria to gentamicin killing

Lvyuan Fan; Zhiyu Pan; Yilin Zhong; Juan Guo; Xu Liao; Rui Pang; Qingqiang Xu; Guozhu Ye; Yubin Su

doi:10.1128/spectrum.01619-23

Microbiology Spectrum (Dec 2023)

L-glutamine sensitizes Gram-positive-resistant bacteria to gentamicin killing

Lvyuan Fan,
Zhiyu Pan,
Yilin Zhong,
Juan Guo,
Xu Liao,
Rui Pang,
Qingqiang Xu,
Guozhu Ye,
Yubin Su

Affiliations

Lvyuan Fan: Department of Cell Biology & Institute of Biomedicine National Engineering Research Center of Genetic Medicine, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology,Jinan University , Guangzhou, China
Zhiyu Pan: Department of Cell Biology & Institute of Biomedicine National Engineering Research Center of Genetic Medicine, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology,Jinan University , Guangzhou, China
Yilin Zhong: Department of Cell Biology & Institute of Biomedicine National Engineering Research Center of Genetic Medicine, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology,Jinan University , Guangzhou, China
Juan Guo: Department of Cell Biology & Institute of Biomedicine National Engineering Research Center of Genetic Medicine, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology,Jinan University , Guangzhou, China
Xu Liao: Center for Excellence in Regional Atmospheric Environment and Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences , Xiamen, China
Rui Pang: Guangdong Provincial Key Laboratory of Microbial Safety and Health,State Key Laboratory of Applied Microbiology Southern China, Guangdong Institute of Microbiology, Guangdong Academy of Sciences , Guangzhou, China
Qingqiang Xu: Department of Cell Biology & Institute of Biomedicine National Engineering Research Center of Genetic Medicine, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology,Jinan University , Guangzhou, China
Guozhu Ye: Center for Excellence in Regional Atmospheric Environment and Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences , Xiamen, China
Yubin Su: Department of Cell Biology & Institute of Biomedicine National Engineering Research Center of Genetic Medicine, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology,Jinan University , Guangzhou, China

DOI: https://doi.org/10.1128/spectrum.01619-23
Journal volume & issue: Vol. 11, no. 6

Abstract

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ABSTRACT Because of the stubborn resistance to antibiotics, treating clinically resistant bacteria is a tricky business. Although considerable attention has been devoted to preventing and treating infections from drug-resistant bacteria, few studies are available on combining metabolites and antibiotics to combat methicillin-resistant Staphylococcus aureus (MRSA). This study found that exogenous L-glutamine potentiated aminoglycoside (gentamicin)-mediated killing efficacy in a dose- and time-dependent manner in MRSA (USA300 cell line) and other Gram-positive-resistant bacteria including MRSA 252, Listeria monocytogenes, and Corynebacterium diphtheriae. L-glutamine promoted the uptake of gentamicin through increasing the membrane permeability and was correlated with disrupted pH gradient. Furthermore, L-glutamine decreased intracellular reactive oxygen species by glutathione, which also increased USA300 sensitivity to gentamicin. We also demonstrated that combined treatment with gentamicin and L-glutamine enhanced the survival of MRSA-infected mice. In conclusion, we developed a promising therapeutic strategy for treating Gram-positive-resistant bacterial infections. IMPORTANCE Methicillin-resistant Staphylococcus aureus (MRSA) infection severely threatens human health due to high morbidity and mortality; it is urgent to develop novel strategies to tackle this problem. Metabolites belong to antibiotic adjuvants which improve the effect of antibiotics. Despite reports of L-glutamine being applied in antibiotic adjuvant for Gram-negative bacteria, how L-glutamine affects antibiotics against Gram-positive-resistant bacteria is still unclear. In this study, L-glutamine increases the antibacterial effect of gentamicin on MRSA, and it links to membrane permeability and pH gradient (ΔpH), resulting in uptake of more gentamicin. Of great interest, reduced reactive oxygen species (ROS) by glutathione was found under L-glutamine treatment; USA300 becomes sensitive again to gentamicin. This study not only offers deep understanding on ΔpH and ROS on bacterial resistance but also provides potential treatment solutions for targeting MRSA infection.

Published in Microbiology Spectrum

ISSN: 2165-0497 (Online)
Publisher: American Society for Microbiology
Country of publisher: United States
LCC subjects: Science: Microbiology
Website: https://journals.asm.org/journal/spectrum

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