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: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192892
• 关键词: Antibiotic Therapy; Antibiotic susceptibility; Antibiotics; Automobile Driving; Bacterial Infections; Cell physiology; Cells; Cessation of life; Chelating Agents; Chronic; Citric Acid Cycle; Coupling; DNA biosynthesis; Diet; Disease; Drops; Environment; Environmental Risk Factor; Evolution; Exhibits; Exposure to; Genetic Transcription; Growth; Homeostasis; Immune; Immune system; In Vitro; Infection; Innate Immune Response; Innate Immune System; Invaded; Knowledge; Leukocyte L1 Antigen Complex; Measures; Mediating; Metabolic; Metabolism; Metals; Micronutrients; Modeling; Nutritional Immunity; Phenotype; Physiological; Population; Predisposition; Process; Protein Biosynthesis; Proteins; Public Health; Reactive Oxygen Species; Regimen; Relapse; Resistance; Resolution; Role; Route; Sepsis; Staphylococcus aureus; Staphylococcus aureus infection; Starvation; Testing; Transition Elements; Translation Process; Translations; Treatment Failure; Zinc; Zinc deficiency; antibiotic tolerance; bactericide; cofactor; genetic manipulation; human pathogen; immunoregulation; improved; in vivo; metalloenzyme; mouse model; pathogen; stressor

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.

摘要