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Elucidating the mechanisms of antibiotic tolerance in Staphylococcus aureus biofilms

阐明金黄色葡萄球菌生物膜的抗生素耐受机制

基本信息

批准号：
10704541
负责人：
Jeffrey Alexander Freiberg
金额：
$ 7.61万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10704541
关键词：
Ablation Address Animal Model Antibiotic Therapy Antibiotic susceptibility Antibiotics Bacteremia Bacteria Bacterial Infections Cessation of life Chronic Complex Daptomycin Development Elements Endocarditis Exposure to Extracellular Matrix Fluorescence Microscopy Foundations Future Genes Genus staphylococcus Growth High Prevalence Image Individual Inductively Coupled Plasma Mass Spectrometry Infection Iron Lasers Lead Literature Manganese Mediating Metals Microbial Biofilms Modeling Morbidity - disease rate Mus Mutation Nutrient Osteomyelitis Oxidative Stress Oxygen Pathogenesis Pattern Penetration Phenotype Play Production Proteins Proteomics Public Health Reactive Inhibition Reactive Oxygen Species Regulation Regulon Research Role Sepsis Shotguns Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Staphylococcus aureus Staphylococcus aureus infection Stress Sum Surface Testing Therapeutic Therapeutic Intervention Transition Elements United States Up-Regulation Variant Virulence Work alternative treatment antibiotic tolerance biological adaptation to stress cell community chronic infection clinically significant differential expression drug development experimental study in vivo insight mass spectrometric imaging methicillin resistant Staphylococcus aureus microbial mortality mutant novel therapeutics response stress tolerance targeted treatment transcriptome transposon sequencing

项目摘要

SUMMARY Staphylococcus aureus is one of the leading causes of bacterial infections in the United States. Invasive S. aureus infections (such as osteomyelitis, endocarditis, and bloodstream infections) are associated with relatively high rates of morbidity and mortality even when treated with appropriate antibiotics. The ability to form biofilms, microbially derived communities where cells grow attached to a surface or as a bacterial conglomerate surrounded by a complex extracellular matrix, has been associated with persistent S. aureus infections. A defining feature of bacterial biofilms, including S. aureus biofilms, is a high tolerance to antibiotics. Despite the clinical significance of the antibiotic tolerance seen in biofilm-mediated infections, the mechanism by which this occurs is poorly understood. Antibiotics have been shown to penetrate S. aureus biofilms, suggesting that there are other mechanisms besides physical occlusion involved in tolerance. One possible explanation for the increase in antibiotic tolerance is an enhanced ability to tolerate oxidative stress, which is seen in biofilm growth. Given the growing body of literature suggesting a role for oxidative stress in antibiotic-mediated killing, we hypothesize that changes in protein production that promote the bacterial oxidative stress response lead to the antibiotic tolerance phenotype seen during biofilm-mediated S. aureus infections. Furthermore, given the important role of the transition metals manganese and iron in S. aureus virulence and the oxidative stress response, we anticipate that the ability to regulate the levels of these metals and their distribution within S. aureus biofilms is integral to the antibiotic tolerance phenotype seen in S. aureus biofilms. In order to test this hypothesis, we will (1) determine the impact of antibiotic exposure on metal regulation and the oxidative stress response in S. aureus biofilms using a combination of fluorescence microscopy along with matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), (2) identify the staphylococcal genes responsible for antibiotic tolerance in biofilm growth using transposon sequencing (TnSeq) and proteomic experiments, and (3) demonstrate the in vivo significance of these findings using an animal model of osteomyelitis, a chronic biofilm-mediated S. aureus infection. The sum of this work will result in not only a better understanding of what the elements are that are responsible for antibiotic tolerance in S. aureus infections, but it will also provide new insight that will be useful in developing therapeutics and treatments aimed at reducing the morbidity and mortality of infections due to S. aureus.

总结