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Title: Rickettsia prowazekii methionine aminopeptidase as a promising target for the development of antibacterial agents

Methionine aminopeptidase (MetAP) is a class of ubiquitous enzymes essential for the survival of numerous bacterial species. These enzymes are responsible for the cleavage of N-terminal formyl-methionine initiators from nascent proteins to initiate post-translational modifications that are often essential to proper protein function. Thus, inhibition of MetAP activity has been implicated as a novel antibacterial target. In this study, we tested this idea in the present study by targeting the MetAP enzyme in the obligate intracellular pathogen Rickettsia prowazekii. We first identified potent RpMetAP inhibitory species by employing an in vitro enzymatic activity assay. The molecular docking program AutoDock was then utilized to compare published crystal structures of inhibited MetAP species to docked poses of RpMetAP. Based on these in silico and in vitro screens, a subset of 17 compounds was tested for inhibition of R. prowazekii growth in a pulmonary vascular endothelial cell (EC) culture infection model system. All compounds were tested over concentration ranges that were determined to be non-toxic to the ECs and 8 of the 17 compounds displayed substantial inhibition of R. prowazekii growth. Lastly, these data highlight the therapeutic potential for inhibiting RpMetAP as a novel antimicrobial strategy and set the stage for future studiesmore » in pre-clinical animal models of infection.« less
Authors:
 [1] ;  [1] ;  [1] ;  [2] ;  [3] ;  [2] ;  [4] ;  [5] ;  [6] ;  [5] ;  [1] ;  [1]
  1. Northern Illinois Univ., DeKalb, IL (United States). Department of Chemistry and Biochemistry
  2. Beryllium Discovery Corp., Bainbridge Island, WA (United States); Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA (United States)
  3. Center for Infectious Disease Research, Seattle, WA (United States); Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA (United States)
  4. Ernest Orlando Lawrence Berkeley National Laboratory, Berkeley, CA (United States); Molecular Biophysics and Integrated Bioimaging, Berkeley Center for Structural Biology
  5. University of South Alabama College of Medicine, Laboratory of Infectious Diseases, Mobile, AL (United States). Department of Microbiology and Immunology and The Center for Lung Biology
  6. Center for Infectious Disease Research, Seattle, WA (United States); Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA (United States); Univ. of Washington, Seattle, WA (United States). Department of Global Health and Department of Biomedical Informatics and Medical Education
Publication Date:
Grant/Contract Number:
AC02-05CH11231
Type:
Accepted Manuscript
Journal Name:
Bioorganic and Medicinal Chemistry
Additional Journal Information:
Journal Volume: 25; Journal Issue: 3; Journal ID: ISSN 0968-0896
Publisher:
Elsevier
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; MetAP; Methionine aminopeptidase; Inhibition; Metalloenzyme; Epidemic typhus; Rickettsia prowazekii; Lung endothelial cells
OSTI Identifier:
1423611
Alternate Identifier(s):
OSTI ID: 1412590