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

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• 作者：Travis R. Helgren^a ; Congling Chen^a ; Phumvadee Wangtrakuldee^a ; Thomas E. Edwards^b ; ^d ; Bart L. Staker^c ; ^d ; Jan Abendroth^b ; ^d ; Banumathi Sankaran^f ; Nicole A. Housley^g ; Peter J. Myler^c ; ^d ; ^e ; Jonathon P. Audia^g ; James R. Horn^a ; Timothy J. Hagen^a ; ^{thagen@niu.edu}
• 关键词：MetAP ; Methionine aminopeptidase ; Inhibition ; Metalloenzyme ; Epidemic typhus ; Rickettsia prowazekii ; Lung endothelial cells
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：25
• 期：3
• 页码：813-824
• 全文大小：2989 K
• 卷排序：25

文摘

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. 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. These data highlight the therapeutic potential for inhibiting RpMetAP as a novel antimicrobial strategy and set the stage for future studies in pre-clinical animal models of infection.