TY - JOUR
T1 - RNAIII-inhibiting peptide in combination with the cathelicidin BMAP-28 reduces lethality in mouse models of staphylococcal sepsis
AU - Ghiselli, Roberto
AU - Giacometti, Andrea
AU - Cirioni, Oscar
AU - Dell'Acqua, Giorgio
AU - Bergnach, Cristina
AU - Orlando, Fiorenza
AU - Mocchegiani, Federico
AU - Silvestri, Carmela
AU - Skerlavaj, Barbara
AU - Licci, Alberto
AU - Balaban, Naomi
AU - Zanetti, Margherita
AU - Scalise, Giorgio
AU - Saba, Vittorio
PY - 2006/9
Y1 - 2006/9
N2 - 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 α 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 α and interleukin 6 plasma levels. BALB/c mice were injected i.v. with 2.0 × 10 colony-forming units of live Staphylococcus aureus ATCC 25923 or with 5.0 × 10 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.
AB - 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 α 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 α and interleukin 6 plasma levels. BALB/c mice were injected i.v. with 2.0 × 10 colony-forming units of live Staphylococcus aureus ATCC 25923 or with 5.0 × 10 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.
KW - Antimicrobial peptide
KW - BMAP-28
KW - RIP
KW - Septic shock
KW - Staphylococcal sepsis
UR - http://www.scopus.com/inward/record.url?scp=33747338356&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33747338356&partnerID=8YFLogxK
U2 - 10.1097/01.shk.0000226336.02292.86
DO - 10.1097/01.shk.0000226336.02292.86
M3 - Article
C2 - 16912656
AN - SCOPUS:33747338356
VL - 26
SP - 296
EP - 301
JO - Shock
JF - Shock
SN - 1073-2322
IS - 3
ER -