RNAIII-inhibiting peptide in combination with the cathelicidin BMAP-28 reduces lethality in mouse models of staphylococcal sepsis.
A mouse model of staphylococcal sepsis was used to evaluate the efficacy of RNAIII-inhibiting peptide (RIP) combined with the cathelicidin BMAP-28. Preliminary in vitro studies showed that both peptides, alone or combined, were able to inhibit the lipoteichoic acid-induced production of tumor necrosis factor alpha and nitric oxide by RAW 264.7 cells. For in vivo experiments, the main outcome measures were lethality, quantitative blood cultures, and detection of tumor necrosis factor alpha and interleukin 6 plasma levels. BALB/c mice were injected i.v. with 2.0 x 10(6) colony-forming units of live Staphylococcus aureus ATCC 25923 or with 5.0 x 10(8) heat-killed cells of the same strain. All animals were randomized to receive i.v. isotonic sodium chloride solution, 10-mg/kg RIP, alone or in combination with 2-mg/kg BMAP-28, 7-mg/kg imipenem, or 7-mg/kg vancomycin, immediately and at 6 hours after bacterial challenge. In in vivo experiments performed with live bacteria, all compounds reduced lethality rates and bacteremia when compared with controls. In general, combined-treated groups had significantly lower bacteremia when compared with single-treated groups. Lowest lethality rates and bacteremia were obtained when RIP was administered in combination with BMAP-28 or vancomycin. In the experiments performed using heat-killed organisms, only BMAP-28 demonstrated significant efficacy on lethality rates and cytokines plasma levels when compared with controls. RIP combined with BMAP-28 exhibited the highest efficacy on all main outcome measurements. These data were observed on both immediate and delayed treatments. These results highlight the capacity of RIP and BMAP-28 to reduce the septic effects of bacterial cell components and exotoxins, and suggest their potential use in the treatment of severe staphylococcus-associated sepsis.
Ghiselli
Roberto
R
Department of General Surgery, Istituto Nazionale Riposo e Cura Anziani-Istituto di Ricovero e Cura a Carattere Scientifico, Università Politecnica delle Marche, Ancona, Italy.
Giacometti
Andrea
A
Cirioni
Oscar
O
Dell'Acqua
Giorgio
G
Bergnach
Cristina
C
Orlando
Fiorenza
F
Mocchegiani
Federico
F
Silvestri
Carmela
C
Skerlavaj
Barbara
B
Licci
Alberto
A
Balaban
Naomi
N
Zanetti
Margherita
M
Scalise
Giorgio
G
Saba
Vittorio
V
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D011506:Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D013203:Staphylococcal Infections / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects; D016019:Survival Analysis; D013682:Teichoic Acids / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; C102360:BMAP-28; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009842:Oligopeptides; D011506:Proteins; C111711:RNAIII inhibiting peptide; D013682:Teichoic Acids; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C009900:lipoteichoic acid