The recent outbreaks of bacterial infections caused by Escherichia coli and Listeria monocytogenes mark the critical importance in the search of new lines of antibiotics. In particular, existing drugs for bacterial infections all target the sam cellular processes, and bacteria are quick to develop resistance to these treatments. One direction for antibiotics design is to manufacture drugs that disrupt other cellular processes not yet targeted, such as cell division, which is a primary process required for cell survival. Yet the lack of understanding of bacterial cell division mechanisms renders such effort difficult. Our proposal aims to provide a detailed, atomistic view on how bacterial cell division is carried out. We will focus on the essential cell division protein, FtsZ, which serves two roles during cell division: generation of mechanical forces that constrict cell width, and the recruitment and coordination of several other cell division proteins. We will combine biochemistry, imaging experiments, and physics-based computational techniques to resolve the molecular interactions that render FtsZ functional, and then genetically manipulate FtsZ to perturb these amino acids and interfere with the cell division process, causing cell death. Our investigation will unveil sits of FtsZ that can be targeted for antibiotic activities, thereby expediting the search for a new generation of antibacterial treatments.

Public Health Relevance

The recent outbreaks of bacterial infections caused by Escherichia coli and Listeria monocytogenes mark the critical importance in the search of new lines of antibiotics, as existing drugs for bacterial infections all target the same cellular processes, and bacteria are quick to develop resistance to these treatments. One direction for antibiotics design is to manufacture drugs that disrupt other cellular processes not yet targeted, such as cell division, which is a primary process required for cell survival, but the lack of understanding of bacterial cell division mechanisms renders such effort difficult. Our proposal aims to provide a detailed, atomistic view on how bacterial cell division is carried out, focusing on unveiling sites of FtsZ, the essential cell division protein, that can be targeted for antibioti activities, thereby expediting the search for a new generation of antibacterial treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM100677-02
Application #
8565647
Study Section
Special Emphasis Panel (ZRG1-F04-D (20))
Program Officer
Flicker, Paula F
Project Start
2012-11-16
Project End
2014-11-15
Budget Start
2013-11-16
Budget End
2014-11-15
Support Year
2
Fiscal Year
2014
Total Cost
$53,942
Indirect Cost
Name
Stanford University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Lee, Timothy K; Tropini, Carolina; Hsin, Jen et al. (2014) A dynamically assembled cell wall synthesis machinery buffers cell growth. Proc Natl Acad Sci U S A 111:4554-9
Colavin, Alexandre; Hsin, Jen; Huang, Kerwyn Casey (2014) Effects of polymerization and nucleotide identity on the conformational dynamics of the bacterial actin homolog MreB. Proc Natl Acad Sci U S A 111:3585-90
Hsin, Jen; Fu, Rui; Huang, Kerwyn Casey (2013) Dimer dynamics and filament organization of the bacterial cell division protein FtsA. J Mol Biol 425:4415-26
Li, Ying; Hsin, Jen; Zhao, Lingyun et al. (2013) FtsZ protofilaments use a hinge-opening mechanism for constrictive force generation. Science 341:392-5