RNAIII inhibiting peptide (RIP), a global inhibitor of Staphylococcus aureus pathogenesis: structure and function analysis

Staphylococcus aureus are gram-positive bacteria that can cause serious dis eases in humans and animals. S. aureus infections can be prevented by the h eptapeptide RNAIII inhibiting peptide (RIP). RIP was originally isolated fr om culture supernatants of coagulase negative staphylococci presumed to be S. xylosus. The sequence of RIP was identified as YSPXTNF. Native RIP and i ts synthetic analogue YSPWTNF have been shown to be effective inhibitors of diseases caused by various strains of S. aureus, including, cellulitis, ke ratitis, septic arthritis, osteomylitis and mastitis. RIP is therefore cons idered to be a global inhibitor of S. aureus. We show here that: 1) the ami de form of RIP (YSPWTNF-NH2) is highly stable and is therefore the one reco mmended for use. 2) RIP inhibits S. aureus pathogenesis by inhibiting the s ynthesis of both agr transcripts RNAII and RNAIII. 3) Although RIP inhibits agr, it also reduces bacterial adherence to mammalian cells and to plastic (tested on HEp2 cells and on polystyrene by fluorescence and atomic force microscopy), suggesting that RIP can be used safely as a therapeutic molecu le. 4) RIP derivatives were designed and tested for their ability to inhibi t RNAIII in vitro and cellulitis in vivo. Not all peptides that inhibited R NAIII also inhibited an infection in vivo, indicating that studies must be carried out in vivo before considering a peptide to be of therapeutic poten tial. 5) The RIP derivative containing Lysine and Isoleucine at positions 2 and 4, respectively, inhibited S. aureus infections in vivo (tested on cel lulitis), suggesting that both RIP YSPWTNF and its derivative YKPITNF are e ffective inhibitors of infections caused by S. aureus. (C) 2001 Elsevier Sc ience Inc. All rights reserved.