The discovery of antibiotics to treat bacterial infections has had a dramatic and positive impact on human health. However shortly after the introduction of new antibiotics, resistance often develops. The emergence and spread of antibiotic resistant bacteria is considered a worldwide health emergency. In addition to a public health threat, antibiotic resistant bacteria also place a significant financial burden on the health care system. It is clear new methods to target antibiotic resistance are seriously needed. The bacterial cell envelope is essential for cell viability and is the target of many of the most commonly used antibiotics including ?-lactam antibiotics like penicillin. These are general broad-spectrum antibiotics that target peptidoglycan biosynthesis by inhibiting the transpeptidase activity of penicillin binding proteins. Our long-term goal is to understand the mechanism by which ?-lactams are sensed by Gram- positive bacteria. Organisms in the Bacillus cereus group including Bacillus thuringiensis and Bacillus anthracis are highly resistant to ?-lactam antibiotics. This resistance is dependent upon the Extra- Cytoplasmic Function (ECF) ? factor ?P, which we have found is specifically activated by a subset of ?- lactam antibiotics. ECF ? factors represent an important class of signal transduction systems which compared to other regulatory systems are relatively poorly understood. We have found that ?P is activated upon the sequential proteolytic destruction of the anti-? factor RsiP. Our data indicate that BT3488 a penicillin binding protein is required for site-1 cleavage of RsiP. These findings raise several important questions: How are ?-lactam antibiotics sensed by the cell? What factors are required for activating ?P in response to ?-lactam antibiotics? Here we propose to 1) Determine the role of BT3488 and RsiP in sensing ?-lactams and controlling ?P activation and 2) Identify additional factors required for ?P activation.

Public Health Relevance

?-lactam antibiotics like penicillin are general broad-spectrum antibiotics that target peptidoglycan biosynthesis in many clinically significant bacteria. Bacterial resistance to ?-lactam antibiotics is a significant health threat. Our studies will lead to a greater understanding of how bacteria sense and respond to ?-lactam antibiotics which may lead to better ways to control the spread of antibiotic resistant bacteria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI146769-02
Application #
9929530
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Huntley, Clayton C
Project Start
2019-05-14
Project End
2021-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Iowa
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242