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Investigation of capsule interactions that promote antimicrobial peptide activity

促进抗菌肽活性的胶囊相互作用的研究

基本信息

批准号：
10378034
负责人：
Bryan William Davies
金额：
$ 23.42万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-19 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10378034
关键词：
Amino Acid Sequence Amino Acids Anti-Bacterial Agents Antibiotic Therapy Antibiotics Bacteria Bacterial Capsules Binding Biochemical Bypass Characteristics Colistin Data Development Electrostatics Goals Gram-Negative Bacteria Host Defense Hydrophobic Interactions Immune Immune Evasion Immune response Individual Infection Innate Immune Response Innate Immune System Investigation Klebsiella pneumoniae Knowledge Lead Length Libraries Mass Spectrum Analysis Membrane Modeling Multi-Drug Resistance Penetration Peptides Play Polymyxins Polysaccharides Resort Structure TRAP Peptide Time Variant Virulence Factors antimicrobial antimicrobial peptide base capsule cell envelope extracellular improved insight novel therapeutic intervention pathogen prevent resistant Klebsiella pneumoniae scaffold synthetic peptide therapeutic development

项目摘要

Project Summary. The extracellular polysaccharide capsule of Klebsiella pneumoniae resists penetration by antimicrobials and protects the bacteria from the innate immune system. While capsule inhibits most host defense peptides and polymyxin antibiotics, a few amphipathic antimicrobial peptides have been identified that retain activity against capsulated K. pneumoniae. However, it is not known what enables some peptides to avoid sequestration by K. pneumoniae capsule while it effectively neutralizes most others. We have uncovered a mechanism that allows synthetic antimicrobial peptides to overcome capsule inhibition. Specific amino acid changes in inactive sequences enable peptides to bind, aggregate, and disrupt capsule layers, leaving K. peumoniae vulnerable to their membrane attack. Through this proposal we will 1) explore this new mechanism in innate immune host defense peptides that kill capsulated K. pneumoniae, and 2) characterize amino acid sequence and positional variations that promote activity towards capsulated bacteria. Our results will provide important insight into immune evasion by K. pneumoniae and other capsulated bacteria, and identify mechanistic principles will aid the development new therapeutic approaches to overcome the capsule barrier.

项目总结。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Export of Diverse and Bioactive Small Proteins through a Type I Secretion System.

DOI：
10.1128/aem.00335-23
发表时间：
2023-05-31
期刊：
Applied and environmental microbiology
影响因子：
4.4
作者：
通讯作者：

Generation of Synthetic Acinetobacter baumannii-Specific Nanobodies.

DOI：
10.1021/acsinfecdis.3c00024
发表时间：
2023-06-09
期刊：
ACS INFECTIOUS DISEASES
影响因子：
5.3
作者：
Knauf, Gregory A.;Groover, Kyra E.;O'Donnell, Angela C.;Davies, Bryan W.
通讯作者：
Davies, Bryan W.

Evidence for Widespread Class II Microcins in Enterobacterales Genomes.

DOI：
10.1128/aem.01486-22
发表时间：
2022-12-13
期刊：
Applied and environmental microbiology
影响因子：
4.4
作者：
通讯作者：

Adapting antibacterial display to identify serum active macrocyclic peptide antibiotics.

采用抗菌显示来识别血清活性大环肽抗生素。

DOI：
10.1101/2023.07.28.550711
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Randall,JustinR;Groover,KyraE;O'Donnell,AngelaC;Garza,JosephM;Cole,TJeffrey;Davies,BryanW
通讯作者：
Davies,BryanW

Synthetic antibacterial discovery of symbah-1, a macrocyclic β-hairpin peptide antibiotic.

DOI：
10.1016/j.isci.2021.103611
发表时间：
2022-01-21
期刊：
iScience
影响因子：
5.8
作者：
Randall JR;Davidson G;Fleeman RM;Acosta SA;Riddington IM;Cole TJ;DuPai CD;Davies BW
通讯作者：
Davies BW