| Amphipathic cationic peptides, as a part of host-defense system, play a criticalrole in defending against microorganism. The characteristics of antimicrobial peptides,including broad spectrum antimicrobial activity, rapid killing, difficulty of inducingdrug resistance, made it possible to be new antibiotics for clinical practices.Helicobacter pylori infection was a major pathogenic factor that caused chronicactive gastritis, peptic ulcer, gastric mucosa associated lymphoid tissue (MALT)lymphoma and gastric cancer. Studies showed that helicobacter pylori was resistant toitself antibacterial activity and the antibacterial activity was determined bycecropin-like N-terminal peptides derived from the ribosomal protein L1(RpL1).HPRP-A1, a15-mer α-helical cationic peptide and rich in lysine and tryptophan, isderived from N-terminus of ribosomal protein L1(RpL1) of Helicobacter pylori.Therefore, it is significant to study peptide analogs derived from N-terminus ofribosomal protein L1(RpL1) of Helicobacter pylori and their antibacterial activity,antifungal activity and mechanism of action.HPRP-A1was used as a framework to obtain a series of peptide analogs withdifferent hydrophobicity by single amino acid substitutions in the center of nonpolarface of the amphipathic helix, in order to study the effect of hydrophobicity onbiological activities of-helical antimicrobial peptides systematically. Our studiesshowed that hydrophobicity and net charge of peptides play key roles in thebiological activities of these peptide analogs; The results are consistent with theproposed antibacterial mechanism that the activities of cationic antibacterial peptidesdepend upon interactions with bacterial cell membrane. In general, peptides firstspread to bacterial cytoplasmic membrane through electrostatic attraction and then the nonpolor face of peptides insert into cytoplasmic membrane through hydrophobicinteraction with membrane. peptides with more net charge and higher hydrophobicitysuch as F8L, F8I, HPRP-A1, F8W have stronger electrostatic attraction and greaterhydrophobic interactions with cytoplasmic membrane, hence they can insert into lipidbilayer of membrane more easily and exert a better antibacterial activity. HPRP-A1and peptide analogs with relative higher hydrophobicity exerted broad spectrumantimicrobial activity against Gram-negative bacteria, Gram-positive bacteria andpathogenic fungi, but also showed stronger hemolytic activity; the change ofhydrophobicity and net charge of peptides had similar effects with close trend andextent on antibacterial activities and antifungal activities. This may indicate that therewere certain correlations between the antibacterial mode of action and the antifungalmode of action of these peptides in this study.The peptides have killing specificity for bacteria and fungi, The killingspecificity mostly depends on differences of interactions between peptides and thelipid components of different cell membranes. Both bacteria and fungi havenegatively charged components on their cell membranes or outer envelope. Incontrast to bacterial and fungal cell membranes, mammalian cell membranes aregenerally characterized by zwitterionic phospholipids, a relatively large amount ofcholesterol and sphingomyelin; hence, electrostatic interactions between bacterial andfungal membranes and cationic peptides are stronger than those between mammalianmembranes and peptides, which may be the reason that cationic peptides have betterkilling effects against bacteria and fungi. The peptides exhibited antimicrobialspecificity for bacteria and fungi, which provide potentials to develop newantimicrobial drugs for clinical practices. |
