Phage-antibiotic synergy suppresses resistance emergence of Klebsiella pneumoniae by altering the evolutionary fitness

Kunhao Qin; Xing Shi; Kai Yang; Qiuqing Xu; Fuxing Wang; Senxiong Chen; Tingting Xu; Jinquan Liu; Wangrong Wen; Rongchang Chen; Zheng Liu; Li Cui; Kai Zhou

doi:10.1128/mbio.01393-24

mBio (Oct 2024)

Phage-antibiotic synergy suppresses resistance emergence of Klebsiella pneumoniae by altering the evolutionary fitness

Kunhao Qin,
Xing Shi,
Kai Yang,
Qiuqing Xu,
Fuxing Wang,
Senxiong Chen,
Tingting Xu,
Jinquan Liu,
Wangrong Wen,
Rongchang Chen,
Zheng Liu,
Li Cui,
Kai Zhou

Affiliations

Kunhao Qin: Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, China
Xing Shi: Shenzhen Institute of Respiratory Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
Kai Yang: Key Laboratory of Urban Environment and Health, Fujian Key Laboratory of Watershed Ecology, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, China
Qiuqing Xu: Shenzhen Institute of Respiratory Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
Fuxing Wang: Kobilka Institute of Innovative Drug Discovery, School of Medicine, Chinese University of Hong Kong, Shenzhen, China
Senxiong Chen: Kobilka Institute of Innovative Drug Discovery, School of Medicine, Chinese University of Hong Kong, Shenzhen, China
Tingting Xu: Shenzhen Institute of Respiratory Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
Jinquan Liu: Shenzhen Institute of Respiratory Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
Wangrong Wen: Clinical Laboratory, The Affiliated Shunde Hospital of Jinan University, Foshan, China
Rongchang Chen: Shenzhen Institute of Respiratory Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
Zheng Liu: Kobilka Institute of Innovative Drug Discovery, School of Medicine, Chinese University of Hong Kong, Shenzhen, China
Li Cui: Key Laboratory of Urban Environment and Health, Fujian Key Laboratory of Watershed Ecology, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, China
Kai Zhou: Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, China

DOI: https://doi.org/10.1128/mbio.01393-24
Journal volume & issue: Vol. 15, no. 10

Abstract

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ABSTRACT Phage-antibiotic synergy (PAS) represents a superior treatment strategy for pathogen infections with less probability of resistance development. Here, we aim to understand the molecular mechanism by which PAS suppresses resistance in terms of population evolution. A novel hypervirulent Klebsiella pneumoniae (KP) phage H5 was genetically and structurally characterized. The combination of H5 and ceftazidime (CAZ) showed a robust synergistic effect in suppressing resistance emergence. Single-cell Raman analysis showed that the phage-CAZ combination suppressed bacterial metabolic activities, contrasting with the upregulation observed with phage alone. The altered population evolutionary trajectory was found to be responsible for the contrasting metabolic activities under different selective pressures, resulting in pleiotropic effects. A pre-existing wcaJ point mutation (wcaJG949A) was exclusively selected by H5, conferring a fitness advantage and up-regulated activity of carbohydrate metabolism, but also causing a trade-off between phage resistance and collateral sensitivity to CAZ. The wcaJ point mutation was counter-selected by H5-CAZ, inducing various mutations in galU that imposed evolutionary disadvantages with higher fitness costs, and suppressed carbohydrate metabolic activity. H5 and H5-CAZ treatments resulted in opposite effects on the transcriptional activity of the phosphotransferase system and the ascorbate and aldarate metabolism pathway, suggesting potential targets for phage resistance suppression. Our study reveals a novel mechanism of resistance suppression by PAS, highlighting how the complexity of bacterial adaptation to selective pressures drives treatment outcomes.IMPORTANCEPhage-antibiotic synergy (PAS) has been recently proposed as a superior strategy for the treatment of multidrug-resistant pathogens to effectively reduce bacterial load and slow down both phage and antibiotic resistance. However, the underlying mechanisms of resistance suppression by PAS have been poorly and rarely been studied. In this study, we tried to understand how PAS suppresses the emergence of resistance using a hypervirulent Klebsiella pneumoniae (KP) strain and a novel phage H5 in combination with ceftazidime (CAZ) as a model. Our study reveals a novel mechanism by which PAS drives altered evolutionary trajectory of bacterial populations, leading to suppressed emergence of resistance. The findings advance our understanding of how PAS suppresses the emergence of resistance, and are imperative for optimizing the efficacy of phage-antibiotic therapy to further improve clinical outcomes.

Published in mBio

ISSN: 2161-2129 (Print); 2150-7511 (Online)
Publisher: American Society for Microbiology
Country of publisher: United States
LCC subjects: Science: Microbiology
Website: https://journals.asm.org/journal/mbio

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