title: 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.
authors: †Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States.
authors: Tucker
authors: T
authors: Maxson
authors: †Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States.|‡Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States.
authors: Caitlin D
authors: CD
authors: Deane
authors: ‡Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States.
authors: Evelyn M
authors: EM
authors: Molloy
authors: ‡Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States.|§Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States.
authors: Courtney L
authors: CL
authors: Cox
authors: ∥Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, Indiana, United States.
authors: Andrew L
authors: AL
authors: Markley
authors: ⊥Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States.
authors: Shaun W
authors: SW
authors: Lee
authors: †Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States.|‡Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States.|§Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States.
authors: Douglas A
authors: DA
authors: Mitchell
mesh_terms: D000595:Amino Acid Sequence; D057055:Aspartic Acid Proteases / Q000037:antagonists & inhibitors; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000494:pharmacology; D059748:Proteolysis; D017386:Sequence Homology, Amino Acid; D013297:Streptococcus pyogenes / Q000187:drug effects / Q000378:metabolism; D013301:Streptolysins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D001426:Bacterial Proteins; D017320:HIV Protease Inhibitors; D011480:Protease Inhibitors; D013301:Streptolysins; C026050:streptolysin S; D057055:Aspartic Acid Proteases