Scholarlink

<p>Amidst the rising antimicrobial resistance in hypervirulent <i>Klebsiella pneumoniae</i> (hvKP), phage therapy has emerged as a promising alternative. However, bacterial resistance to phages remains a critical challenge, with virulence attenuation representing a key characteristic of phage-resistant strains, albeit through incompletely elucidated mechanisms. This study investigated the phage-host interaction between phage vB_LZ2044 and hvKP strain NTUH-K2044, yielding a phage-resistant mutant PR_K2044. Comparative analysis revealed marked virulence attenuation in PR_K2044, accompanied by significant alterations in virulence-associated phenotypes, including capsular polysaccharide (CPS) production, lipopolysaccharide (LPS) integrity, urea metabolism, biofilm formation, and siderophore activity. Whole-genome sequencing (WGS) identified a singular nonsynonymous mutation (Ser332Leu) in the capsular synthesis regulator <i>WcaJ</i>. Transcriptomic analysis demonstrated coordinated regulation of multiple virulence-associated genes, including: CPS related genes (<i>magA</i>, <i>wza</i>, <i>wzb</i>, <i>wzc</i>, <i>gnd</i>, <i>ugd</i>, <i>manB</i>), LPS related genes (<i>glf</i>, <i>wbbN</i>, <i>wbbO</i>, <i>wbbM</i>, <i>wzt</i>, <i>wabH</i>), pili related genes (<i>fimA</i>, <i>mrkC</i>), outer membrane protein associated genes (<i>ompA</i>, <i>acrB</i>), nitrogen metabolism related genes (<i>gcl</i>, <i>hyi</i>, <i>glxR</i>, <i>allB</i>, <i>allC</i>, <i>ureA</i>), biofilm related gene <i>fabZ</i> and siderophore related gene <i>ybtS</i>. Our investigation integrating genomic, transcriptomic, and phenotypic analyses elucidates potential mechanisms underlying virulence attenuation and coordinated reprogramming in phage-resistant hvKP, providing critical insights for optimizing phage-based therapeutic strategies against multidrug-resistant pathogens and underscoring the need to consider adaptive trajectories when evaluating the therapeutic promise and evolutionary consequences of phage therapy.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

The Single Amino Acid Substitution in WcaJ(Ser332Leu) Promotes Hypervirulent Klebsiella Pneumoniae Resistant to Bacteriophage and Virulence Attenuated

  • 期刊论文

  • 发表日期：

    2026年7月7日

查看全文
  • Lingrui Shi,
  • Zhen Li,
  • Li Xiang,
  • Shiqi Tang,
  • Hang Lai,
  • Jiang Wu,
  • Yingshun Zhou,
  • Li Fu

摘要

Amidst the rising antimicrobial resistance in hypervirulent Klebsiella pneumoniae (hvKP), phage therapy has emerged as a promising alternative. However, bacterial resistance to phages remains a critical challenge, with virulence attenuation representing a key characteristic of phage-resistant strains, albeit through incompletely elucidated mechanisms. This study investigated the phage-host interaction between phage vB_LZ2044 and hvKP strain NTUH-K2044, yielding a phage-resistant mutant PR_K2044. Comparative analysis revealed marked virulence attenuation in PR_K2044, accompanied by significant alterations in virulence-associated phenotypes, including capsular polysaccharide (CPS) production, lipopolysaccharide (LPS) integrity, urea metabolism, biofilm formation, and siderophore activity. Whole-genome sequencing (WGS) identified a singular nonsynonymous mutation (Ser332Leu) in the capsular synthesis regulator WcaJ. Transcriptomic analysis demonstrated coordinated regulation of multiple virulence-associated genes, including: CPS related genes (magA, wza, wzb, wzc, gnd, ugd, manB), LPS related genes (glf, wbbN, wbbO, wbbM, wzt, wabH), pili related genes (fimA, mrkC), outer membrane protein associated genes (ompA, acrB), nitrogen metabolism related genes (gcl, hyi, glxR, allB, allC, ureA), biofilm related gene fabZ and siderophore related gene ybtS. Our investigation integrating genomic, transcriptomic, and phenotypic analyses elucidates potential mechanisms underlying virulence attenuation and coordinated reprogramming in phage-resistant hvKP, providing critical insights for optimizing phage-based therapeutic strategies against multidrug-resistant pathogens and underscoring the need to consider adaptive trajectories when evaluating the therapeutic promise and evolutionary consequences of phage therapy.