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HIV protease inhibitors block streptolysin S production.

Abstract：

:Streptolysin S (SLS) is a post-translationally modified peptide cytolysin that is produced by the human pathogen Streptococcus pyogenes. SLS belongs to a large family of azole-containing natural products that are biosynthesized via an evolutionarily conserved pathway. SLS is an important virulence factor during S. pyogenes infections, but despite an extensive history of study, further investigations are needed to clarify several steps of its biosynthesis. To this end, chemical inhibitors of SLS biosynthesis would be valuable tools to interrogate the various maturation steps of both SLS and biosynthetically related natural products. Such chemical inhibitors could also potentially serve as antivirulence therapeutics, which in theory may alleviate the spread of antibiotic resistance. In this work, we demonstrate that FDA-approved HIV protease inhibitors, especially nelfinavir, block a key proteolytic processing step during SLS production. This inhibition was demonstrated in live S. pyogenes cells and through in vitro protease inhibition assays. A panel of 57 nelfinavir analogs was synthesized, leading to a series of compounds with improved anti-SLS activity while illuminating structure-activity relationships. Nelfinavir was also found to inhibit the maturation of other azole-containing natural products, namely those involved in listeriolysin S, clostridiolysin S, and plantazolicin production. The use of nelfinavir analogs as inhibitors of SLS production has allowed us to begin examining the proteolysis event in SLS maturation and will aid in further investigations of the biosynthesis of SLS and related natural products.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Maxson T,Deane CD,Molloy EM,Cox CL,Markley AL,Lee SW,Mitchell DA

doi

10.1021/cb500843r

subject

Has Abstract

pub_date

2015-05-15 00:00:00

pages

1217-26

issue

5

eissn

1554-8929

issn

1554-8937

journal_volume

10

pub_type

杂志文章

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