A synthetic congener modeled on a microbicidal domain of thrombin- induced platelet microbicidal protein 1 recapitulates staphylocidal mechanisms of the native molecule.
Thrombin-induced platelet microbicidal protein 1 (tPMP-1) is a staphylocidal peptide released by activated platelets. This peptide initiates its microbicidal activity by membrane permeabilization, with ensuing inhibition of intracellular macromolecular synthesis. RP-1 is a synthetic congener modeled on the C-terminal microbicidal alpha-helix of tPMP-1. This study compared the staphylocidal mechanisms of RP-1 with those of tPMP-1, focusing on isogenic tPMP-1-susceptible (ISP479C) and -resistant (ISP479R) Staphylococcus aureus strains for the following quantitative evaluations: staphylocidal efficacy; comparative MIC; membrane permeabilization (MP) and depolarization; and DNA, RNA, and protein synthesis. Although the proteins had similar MICs, RP-1 caused significant killing of ISP479C (<50% survival), correlating with extensive MP (>95%) and inhibition of DNA and RNA synthesis (>90%), versus substantially reduced killing of ISP479R (>80% survival), with less MP (55%) and less inhibition of DNA or RNA synthesis (70 to 80%). Interestingly, RP-1-induced protein synthesis inhibition was equivalent in both strains. RP-1 did not depolarize the cell membrane and caused a relatively short postexposure growth inhibition. These data closely parallel those previously reported for tPMP-1 against this strain set and exemplify how synthetic molecules can be engineered to reflect structure-activity relationships of functional domains in native host defense effector molecules.
Xiong
Yan Q
YQ
Department of Medicine, Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 West Carson Street, RB-2, Room 231, Torrance, CA 90502, USA. yxiong@ucla.edu
Bayer
Arnold S
AS
Elazegui
Lisa
L
Yeaman
Michael R
MR
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis; D002463:Cell Membrane Permeability / Q000187:drug effects; D004269:DNA, Bacterial / Q000096:biosynthesis; D008564:Membrane Potentials / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D050506:Mutant Chimeric Proteins / Q000138:chemical synthesis* / Q000494:pharmacology*; D009675:Novobiocin / Q000494:pharmacology; D012329:RNA, Bacterial / Q000096:biosynthesis; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism; D001620:beta-Thromboglobulin / Q000737:chemistry* / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D050506:Mutant Chimeric Proteins; C061615:PPBP protein, human; D012329:RNA, Bacterial; D001620:beta-Thromboglobulin; D009675:Novobiocin