Pseudomonas aeruginosa (Pa) is major Gram-negative pathogen accounting for 10% of all nosocomial infections, including 17% of pneumonia cases. Pa is of particular concern for patients hospitalized with severe burns, cancer or AIDS, for recipients of organ transplants and individuals with cystic fibrosis (CF). Mortality rates are alarmingly high. The steady and inexorable increase of resistance in this organism toward multiple classes of antibiotics, including fourth-generation cephalosporins, has severely limited treatment options and there is now an urgent need for new antimicrobials directed against this pathogen. We seek to address this need by targeting penicillin-binding proteins (PBPs) of Pa for drug discovery. The validity and accessibility of PBPs as drug targets is exemplified by the transformative success of ?-lactam antibiotics in the 20th century, but we are now entering a new era in which the clinical utility of these agents is waning. In Pa, a major mechanism of resistance against ?-lactams is the expression of ?-lactamases, which hydrolyze the antibiotic before it can reach its PBP target. Our overall goal is to restore PBPs as targets for antimicrobials by deployment of non- ?-lactam inhibitors that, by definition, would not be substrates for ?- lactamases. In this R21 application, we propose two requisite steps toward that goal: (1) Among the nine detectable in the Pa genome, identify the PBPs that are legitimate drug targets and (2) Using a fluorescence-polarization assay developed in our laboratory, conduct high-throughput screening to find novel inhibitors of these PBPs. The outcome will be a set of candidate inhibitors that can be later optimized via chemical modification to improve their potency and drug-like properties, with the longer-term goal of developing these as therapeutic agents against Pa.

Public Health Relevance

Pseudomonas aeruginosa is a major hospital pathogen that poses a particular threat for patients with severe burns, cancer or AIDS, recipients of organ transplants or those with cystic fibrosis (CF), and treatment options are becoming increasingly limited due to a steady and inexorable rise in antibiotic resistance, including resistance to fourth-generation cephalosporins. This application will address the increasing threat posed by P. aeruginosa by targeting its penicillin-binding proteins (PBPs) for drug discovery. The valid drug targets amongst the set of P. aeruginosa PBPs will first be determined, followed by high-throughput screening to identify novel inhibitors that will be later developed into anti-pseudomonal agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI109385-01A1
Application #
8771760
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Korpela, Jukka K
Project Start
2014-08-08
Project End
2016-07-31
Budget Start
2014-08-08
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$224,250
Indirect Cost
$74,250
Name
Medical University of South Carolina
Department
Biochemistry
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425