title: Bacterial membrane disrupting dodecapeptide SC4 improves survival of mice challenged with Pseudomonas aeruginosa.
abstract: BACKGROUND
  Dodecapeptide SC4 is a broad-spectrum bactericidal agent that functions by disintegrating bacterial membranes and neutralizing endotoxins. For insight into which SC4 amino acids are functionally important, we assessed Gram-negative bactericidal effects in structure-activity relationship experiments. Subsequently, SC4 was tested in a murine bacteremia model to combine and compare the efficacy with Zosyn, a first-line antibiotic against Pseudomonas aeruginosa (P. aeruginosa).
  
  
  METHODS
  SC4 alanine-scanning analogs and their activities on were tested on P. aeruginosa. Survival studies in P. aeruginosa challenged mice were executed to monitor overall efficacy of SC4 and Zosyn, as a single modality and also as combination treatment. ELISAs were used to measure blood serum levels of selected inflammatory cytokines during treatment.
  
  
  RESULTS
  Cationic residues were found to play a crucial role in terms of bactericidal activity against P. aeruginosa. In vivo, while only 9% (3/34) of control animals survived to day two and beyond, 44% (12/27) to 41% (14/34) of animals treated with SC4 or Zosyn, respectively, survived beyond one week. Combination treatment of SC4 and Zosyn demonstrated improved survival, i.e. 60% (12/20). The TNFα, IL-1, and IL-6 serum levels were attenuated in each treatment group compared to the control group.
  
  
  CONCLUSIONS
  These data show that combination treatment of SC4 and Zosyn is most effective at killing P. aeruginosa and attenuating inflammatory cytokine levels in vivo.
  
  
  CONCLUSIONS
  Combination treatment of SC4 and Zosyn may be useful in the clinic as a more effective antibiotic therapy against Gram-negative infectious diseases.
authors: Department of Biochemistry, University of Minnesota Health Science Center, Minneapolis, MN 55455, USA.
authors: Ruud P M
authors: RP
authors: Dings
authors: Judith R
authors: JR
authors: Haseman
authors: Dan B
authors: DB
authors: Leslie
authors: Mike
authors: M
authors: Luong
authors: David L
authors: DL
authors: Dunn
authors: Kevin H
authors: KH
authors: Mayo
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016470:Bacteremia / Q000097:blood / Q000188:drug therapy*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000097:blood; D008297:Male; D051379:Mice; D010397:Penicillanic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010878:Piperacillin / Q000494:pharmacology; D000077725:Piperacillin, Tazobactam Drug Combination; D011552:Pseudomonas Infections / Q000097:blood / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; D018836:Inflammation Mediators; D010446:Peptide Fragments; C483878:SC-4 peptide; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin
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