title: Novel inhibitor of bacterial sphingomyelinase, SMY-540, developed based on three-dimensional structure analysis.
abstract: BACKGROUND
  Bacterial sphingomyelinase (SMase) is thought to play a crucial role in bacterial evasion of the immune response during the early stages of infections.
  
  
  OBJECTIVE
  The objective of this study was to predict the chemical structure required for competitive SMase inhibition, then synthesize and test the effect of potential inhibitors on the hydrolysis of sphingomyelin (SM) and protection against infection by Bacillus cereus.
  
  
  METHODS
  We synthesized 10 potential SMase inhibitors, derivatives of RY221B-a analogues, based on predictions from three-dimensional structural analysis. We then tested the effect of these compounds on the inhibition of SM hydrolysis and protection of mice inoculated with B. cereus.
  
  
  RESULTS
  One compound, SMY-540, displayed a strong inhibitory effect (IC₅₀ = 0.8 μM) upon SMase and prevented mortality in mice.
  
  
  CONCLUSIONS
  SMY-540 is an effective inhibitor of Bc-SMase and has potential for use in the development of drugs to treat infectious diseases caused by bacteria that produce SMase.
authors.affiliation: Department of Microbiology and.
authors.forename: Masataka
authors.initials: M
authors.lastname: Oda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Imagawa
authors.forename: Ryoko
authors.initials: R
authors.lastname: Kato
authors.forename: Kenta
authors.initials: K
authors.lastname: Yabiku
authors.forename: Tomomi
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Takayuki
authors.initials: T
authors.lastname: Takemoto
authors.forename: Hironobu
authors.initials: H
authors.lastname: Takahashi
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Mugio
authors.initials: M
authors.lastname: Nishizawa
authors.forename: Jun
authors.initials: J
authors.lastname: Sakurai
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nagahama
mesh_terms: D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001409:Bacillus cereus / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity; D001412:Bacillus subtilis / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015870:Gene Expression; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D062105:Molecular Docking Simulation; D011412:Propanolamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000737:chemistry; D013329:Structure-Activity Relationship; D016019:Survival Analysis
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D011412:Propanolamines; C554926:RY221B-a; D011994:Recombinant Proteins; C000594205:SMY-540; D013109:Sphingomyelins; D015082:2,2'-Dipyridyl; D013108:Sphingomyelin Phosphodiesterase; D013110:Sphingosine
keywords: Bacillus cereus; SMY-540; inhibitor; sphingomyelinase