Pseudomonas aeruginosa is a Gram negative bacterium which poses a serious threat to immunocompromised patients as well as those with cystic fibrosis. Resistance of this bacterial pathogen to antibiotics is the main cause of therapeutic failure. B-lactams are important anti-pseudomonas antibiotics and bacterial resistance to this class of antibiotics involves multiple mechanisms, but occurs primarily through overexpression of class C ?-lactamase (AmpC), which is insensitive to ?-lactamase inhibitors currently used in clinic. We have recently identified and characterized the ampG gene in this bacterium, which encodes a membrane transporter involved in cell wall recycling and is essential for the ampC expression. Interestingly, P. aeruginosa with ampG mutation is much more sensitive to ?-lactams than the ampC mutant, indicating that the AmpG is required for multiple mechanisms of ?-lactam resistance. Consistent with this, sensitivity to ?-lactams can be restored among pan-?-lactam resistant clinical isolates of P. aeruginosa by knocking out their ampG genes, demonstrating AmpG is an ideal target for the control of resistance. In this proposal, we intend to elucidate the molecular mechanisms of AmpG-dependent resistance against ?-lactams and identify effective AmpG inhibitors for clinical application. As cell wall recycling is a common process among Gram Negative bacteria, the AmpG inhibitors will be effective against broad spectrum of bacteria. Effective AmpG inhibitors can help us to fight against ?-lactam resistant pathogens while bring ineffective ?-lactams to life, expanding our arsenals against the deadly bacterial infections.

Public Health Relevance

An environmental bacterium called Pseudomonas aeruginosa causes deadly infections among patients with reduced immunity or Cystic Fibrosis. Resistance of this bacterium to antibiotics is the major cause of therapeutic failure. Penicillin class of antibiotics are the best antimicrobials and widely used in hospitals, however, this bacterium can easily become resistant to this class of antibiotics through various mechanisms. Interestingly, a newly identified gene called ampG is required for multiple mechanisms of resistance against the penicillins, making this an ideal target for the control of antibiotic resistance. In this proposal we intend to uncover the molecular details of AmpG-mediated control of the resistance and identify chemical compounds that can block AmpG function, with the ultimate goal of developing new combinatory antimicrobial drugs which not only can control pathogens that are already resistant to penicillins but also bring ineffective penicillins back to life in clinics.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI119043-01
Application #
8951705
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Taylor, Christopher E,
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Florida
Department
Genetics
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611