Scholarlink

<p>Our understanding of the rapid adaptation of bacteria to resist novel drugs is growing beyond known mechanisms such as mobile genetic elements and mutation selection. Heteroresistance (HR) is a form of antibiotic resistance where a phenotypically unstable minority resistant subpopulation co-exists with a susceptible population. We sought to uncover the mechanism of heteroresistance to cefiderocol, a novel β-lactam developed to resist β-lactamases including extended-spectrum-β-lactamases (ESBLs), which has been recently reported but poorly understood. We observe HR to cefiderocol among clinical isolates collected before its use. The resistant subpopulation in <i>Enterobacter</i> is a continuum; increasing copy number of a gene encoding an ESBL ineffective against cefiderocol mediates increased resistance in decreasing numbers of cells. We then pursued the factors that control the magnitude of amplification. We observe that ESBL activity correlates with the level of amplification, and thus that increased copy number can compensate for poor enzymatic activity. A <i>Klebsiella</i> isolate from a clinical treatment failure also demonstrates amplification, highlighting the potential relevance of this β-lactamase gene amplification-mediated HR. These data provide insights into factors controlling dynamics of HR and how bacteria can use gene amplification to flexibly confront new antibiotic threats.</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

Copy number flexibility facilitates heteroresistance to increasing antibiotic pressure and threatens the beta-lactam pipeline

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月1日

查看全文
  • Jacob E. Choby,
  • Tugba Ozturk,
  • Carter N. Abbott,
  • Christina Nnabuife,
  • Jennifer M. Colquhoun,
  • Sarah W. Satola,
  • Philip N. Rather,
  • Timothy Palzkill,
  • David S. Weiss

摘要

Our understanding of the rapid adaptation of bacteria to resist novel drugs is growing beyond known mechanisms such as mobile genetic elements and mutation selection. Heteroresistance (HR) is a form of antibiotic resistance where a phenotypically unstable minority resistant subpopulation co-exists with a susceptible population. We sought to uncover the mechanism of heteroresistance to cefiderocol, a novel β-lactam developed to resist β-lactamases including extended-spectrum-β-lactamases (ESBLs), which has been recently reported but poorly understood. We observe HR to cefiderocol among clinical isolates collected before its use. The resistant subpopulation in Enterobacter is a continuum; increasing copy number of a gene encoding an ESBL ineffective against cefiderocol mediates increased resistance in decreasing numbers of cells. We then pursued the factors that control the magnitude of amplification. We observe that ESBL activity correlates with the level of amplification, and thus that increased copy number can compensate for poor enzymatic activity. A Klebsiella isolate from a clinical treatment failure also demonstrates amplification, highlighting the potential relevance of this β-lactamase gene amplification-mediated HR. These data provide insights into factors controlling dynamics of HR and how bacteria can use gene amplification to flexibly confront new antibiotic threats.