Targeting bacterial cell division with small molecules and peptides

用小分子和肽靶向细菌细胞分裂

基本信息

项目摘要

Resistance to antibacterial therapies continues to be an urgent threat to human health, particularly bacteria that are already resistant to multiple antibiotics. To discover and develop new antibacterials, it is important to find and exploit under-utilized antibiotic targets. One attractive candidate is the divisome, the dynamic protein complex that splits bacterial cells in two. The bacterial divisome contains a set of highly conserved and essential proteins that act coordinately to ensure the correct timing and placement of the cell division septum at mid-cell. The septal transpeptidase is already a target of several widely used beta-lactam antibiotics, but no other divisome protein is currently targeted. FtsZ, a highly conserved polymer-forming GTPase that forms a membrane-associated "Z ring" required for organizing the septal transpeptidase and other septum-synthesizing enzymes, is the only other divisome protein that has been studied extensively as a target of small molecules and peptides, and our lab has helped to advance the understanding of FtsZ and its interacting proteins for 30 years. Nevertheless, there is still much to learn about how small molecules perturb FtsZ function at the molecular and cellular level and whether these can lead to potential therapeutics. To address this over-arching theme, this proposal seeks to define, structurally and physiologically, two different sets of promising new small molecule inhibitors of FtsZ. The first is a set of two related benzamide derivatives, synthesized by our medicinal chemistry collaborators, that have high potencies against both Gram-positive bacteria and Gramnegative bacteria with disabled efflux pumps. These derivatives were synthesized to have optimized binding to the interdomain cleft (IDC) of FtsZ, a common target of inhibitors that we have termed FtsZ's "Achilles Heel". Unexpectedly, we found that these two compounds perturb FtsZ by distinct mechanisms in Gram-positive versus Gram-negative bacteria, prompting the hypothesis that they disrupt FtsZ's ability to assemble into the proper condensed polymer architecture needed for cell division to progress further. This model will be tested with our laboratory's unique interdisciplinary array of genetic, cytological, and structural biology methods. The second set of small molecule inhibitors is a pair of bacteriophage peptides that have evolved to target FtsZ as part of their lytic cycle. Each peptide binds directly to FtsZ and blocks Z ring assembly, but also binds to another essential divisome protein that tethers FtsZ to the cytoplasmic membrane. The molecular details of these binding sites are unknown, but we hypothesize that they do not involve the FtsZ IDC and instead perturb Z ring assembly by novel two-pronged mechanisms. Again, we will apply our extensive expertise in genetics, microscopy and structural biology of divisome proteins to elucidate these mechanisms. The insights we will gain from the proposed studies should lay a foundation for the future therapeutic potential of small molecules and peptides, potentially in combination with each other or with other antibiotics, to kill bacteria by disrupting the cell division machinery.
对抗菌疗法的耐药性仍然是对人类健康,特别是细菌健康的紧迫威胁

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Benzodioxane-Benzamides as FtsZ Inhibitors: Effects of Linker's Functionalization on Gram-Positive Antimicrobial Activity.
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WILLIAM MARGOLIN其他文献

WILLIAM MARGOLIN的其他文献

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{{ truncateString('WILLIAM MARGOLIN', 18)}}的其他基金

Targeting bacterial cell division with small molecules and peptides
用小分子和肽靶向细菌细胞分裂
  • 批准号:
    10510080
  • 财政年份:
    2022
  • 资助金额:
    $ 19.5万
  • 项目类别:
Mechanisms and Regulation of Cell Division in Bacteria
细菌细胞分裂的机制和调控
  • 批准号:
    10373994
  • 财政年份:
    2019
  • 资助金额:
    $ 19.5万
  • 项目类别:
Mechanisms and Regulation of Cell Division in Bacteria
细菌细胞分裂的机制和调控
  • 批准号:
    10590641
  • 财政年份:
    2019
  • 资助金额:
    $ 19.5万
  • 项目类别:
Mechanisms and regulation of cell division in bacteria
细菌细胞分裂的机制和调控
  • 批准号:
    10379704
  • 财政年份:
    2019
  • 资助金额:
    $ 19.5万
  • 项目类别:
Mechanisms and Regulation of Cell Division in Bacteria
细菌细胞分裂的机制和调控
  • 批准号:
    9899263
  • 财政年份:
    2019
  • 资助金额:
    $ 19.5万
  • 项目类别:
Targeting and assembly of E. coli cell division proteins
大肠杆菌细胞分裂蛋白的靶向和组装
  • 批准号:
    7924945
  • 财政年份:
    2009
  • 资助金额:
    $ 19.5万
  • 项目类别:
Targeting and assembly of E. coli division proteins
大肠杆菌分裂蛋白的靶向和组装
  • 批准号:
    8303555
  • 财政年份:
    2000
  • 资助金额:
    $ 19.5万
  • 项目类别:
Targeting and assembly of E. coli cell division proteins
大肠杆菌细胞分裂蛋白的靶向和组装
  • 批准号:
    7283076
  • 财政年份:
    2000
  • 资助金额:
    $ 19.5万
  • 项目类别:
TARGETING AND ASSEMBLY OF E COLI CELL DIVISION PROTEINS
大肠杆菌细胞分裂蛋白的靶向和组装
  • 批准号:
    6797121
  • 财政年份:
    2000
  • 资助金额:
    $ 19.5万
  • 项目类别:
TARGETING AND ASSEMBLY OF E COLI CELL DIVISION PROTEINS
大肠杆菌细胞分裂蛋白的靶向和组装
  • 批准号:
    6651137
  • 财政年份:
    2000
  • 资助金额:
    $ 19.5万
  • 项目类别:

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New technologies for targeted delivery of anti-bacterial agents
抗菌药物靶向递送新技术
  • 批准号:
    1654774
  • 财政年份:
    2015
  • 资助金额:
    $ 19.5万
  • 项目类别:
    Studentship
Targeting bacterial phosphatases for novel anti-bacterial agents.
针对细菌磷酸酶的新型抗菌剂。
  • 批准号:
    8416313
  • 财政年份:
    2012
  • 资助金额:
    $ 19.5万
  • 项目类别:
Targeting bacterial phosphatases for novel anti-bacterial agents.
针对细菌磷酸酶的新型抗菌剂。
  • 批准号:
    8298885
  • 财政年份:
    2012
  • 资助金额:
    $ 19.5万
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