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

Qin, Kunhao1,2,3,4; Shi, Xing2,3; Yang, Kai5; Xu, Qiuqing2,3; Wang, Fuxing6; Chen, Senxiong6; Xu, Tingting2,3; Liu, Jinquan2,3; Wen, Wangrong7,8; Chen, Rongchang2,3; Liu, Zheng6; Cui, Li5; Zhou, Kai1,2,3

2024-09-01

10.1128/mbio.01393-24

MBIO   影响因子和分区

2150-7511

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.

hypervirulent Klebsiella pneumoniae phage-antibiotic synergy evolutionary trajectory metabolic activity

SCI

英语

通讯

MOST | National Key Research and Development Program of China (NKPs)["2021YFC2300300","2022YFE0103200"] ; National Key R&D Program of China[ZDBS-LY-DQC027] ; Chinese Academy of Sciences["82102461","22206184","22176186","82172330"] ; National Natural Science Foundation of China[JCYJ20200109144220704] ; Shenzhen Basic Research Key projects["JCYJ20210324114213038","JCYJ20220530152800001"] ; Shenzhen Basic Research projects[2024A1515030182]

Microbiology

Microbiology

WOS:001309019500011

AMER SOC MICROBIOLOGY

Web of Science

1.Shenzhen Univ, Med Sch, Dept Pathogen Biol, Shenzhen, Peoples R China
2.Jinan Univ, Shenzhen Peoples Hosp, Shenzhen Inst Resp Dis, Clin Med Coll 2, Guangzhou, Peoples R China
3.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen, Peoples R China
4.Jinggangshan Univ, Clin Med Res Ctr, Jiangxi Prov Key Lab Organ Dev & Epigenet, Affiliated Hosp,Hlth Sci Ctr,Med Dept, Jian, Peoples R China
5.Chinese Acad Sci, Inst Urban Environm, Key Lab Urban Environm & Hlth, Fujian Key Lab Watershed Ecol, Xiamen, Peoples R China
6.Chinese Univ Hong Kong, Kobilka Inst Innovat Drug Discovery, Sch Med, Shenzhen, Peoples R China
7.Jinan Univ, Affiliated Shunde Hosp, Clin Lab, Foshan, Peoples R China
8.Jinan Univ, Affiliated Hosp 1, Clin Lab Ctr, Guangzhou, Peoples R China

Qin, Kunhao,Shi, Xing,Yang, Kai,et al. Phage-antibiotic synergy suppresses resistance emergence of Klebsiella pneumoniae by altering the evolutionary fitness[J]. MBIO,2024.

Qin, Kunhao.,Shi, Xing.,Yang, Kai.,Xu, Qiuqing.,Wang, Fuxing.,...&Zhou, Kai.(2024).Phage-antibiotic synergy suppresses resistance emergence of Klebsiella pneumoniae by altering the evolutionary fitness.MBIO.

Qin, Kunhao,et al."Phage-antibiotic synergy suppresses resistance emergence of Klebsiella pneumoniae by altering the evolutionary fitness".MBIO (2024).