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Identifying the contribution of zinc limitation to antibiotic tolerance during S. aureus infection

Identifying the contribution of zinc limitation to antibiotic tolerance during S. aureus infection
确定金黄色葡萄球菌感染期间锌限制对抗生素耐受性的影响
批准号:
10192892
负责人:
Brian Patrick Conlon
金额:
$24.09万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-02-01 至 2023-01-31

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英文摘要
Abstract Staphylococcus aureus is a major human pathogen responsible for numerous chronic and relapsing infections. These infections often do not respond to treatment, leading to approximately 20,000 annual deaths in the US alone. Paradoxically, during in vitro susceptibility testing, isolates from these infections frequently exhibit full sensitivity to administered antibiotics, suggesting that environmental factors present in the host may influence S. aureus antibiotic susceptibility. Understanding how these factors control antibiotic susceptibility will improve the resolution of recalcitrant S. aureus infection, and slow the evolution of resistance. We have previously shown that extrinsic stressors within the host including exposure to reactive oxygen species (ROS) produced by the host innate immune system inadvertently render subpopulations of S. aureus tolerant to antibiotic killing by suppressing S. aureus metabolic activity. However, ROS exposure cannot fully account for the tolerant state of S. aureus in vivo, suggesting that other unidentified factors present within the host reduce antibiotic efficacy against S. aureus. Here we propose that the host immune protein calprotectin induces an antibiotic tolerant state in S. aureus by starving the pathogen of zinc. Zinc is an essential cofactor required for the activity of numerous bacterial metalloenzymes that carry out the major host processes. Zinc- starved populations of S. aureus demonstrate significantly reduced rates of DNA synthesis, transcription, and translation, and these processes represent the primary targets of bactericidal antibiotic action. Host-mediated zinc sequestration may therefore inadvertently render S. aureus tolerant to antibiotic killing by reducing the activity of major antibiotic targets. Overall, we hypothesize that zinc limitation induces an antibiotic tolerant state in S. aureus during infection and that altering zinc availability through diet or immune modulation will influence antibiotic efficacy within the host. In AIM1 we will probe the role of target inactivation in driving S. aureus antibiotic tolerance by directly reducing global DNA replication and translation rates, and measuring the impact on S. aureus antibiotic susceptibility. We will then assess the contribution of host-mediated zinc sequestration in inducing this phenotype. In AIM2 we will move into a mouse model of S. aureus sepsis to assess the relevance of altering physiological zinc availability (through diet or genetic manipulation) to enhance or suppress antibiotic efficacy against S. aureus. In all, we expect that our findings will help improve our understanding of SA antibiotic susceptibility, and elucidate how such knowledge can be exploited to resolve currently unresolvable infections.
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The contribution of respiratory burst to antibiotic failure in Staphylococcus aureus bacteremia
  • 批准号:
    10666777
  • 项目类别:
  • 资助金额:
    $67.46万
  • 财政年份:
    2022
  • 负责人:
    Brian Patrick Conlon
  • 依托单位:
Diabetes and Antibiotic Treatment Failure
  • 批准号:
    10564510
  • 项目类别:
  • 资助金额:
    $71.21万
  • 财政年份:
    2022
  • 负责人:
    Brian Patrick Conlon
  • 依托单位:
Antibiotic activities against S. aureus during P. aeruginosa co-infection
  • 批准号:
    10318912
  • 项目类别:
  • 资助金额:
    $38.47万
  • 财政年份:
    2018
  • 负责人:
    Brian Patrick Conlon
  • 依托单位:
Antibiotic activities against S. aureus during P. aeruginosa co-infection
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