Truncated Autoinducing Peptide Conjugates Selectively Recognize and Kill Staphylococcus aureus.
The accessory gene regulator (agr) of Staphylococcus aureus coordinates various pathogenic events and is recognized as a promising therapeutic target for virulence control. S. aureus utilizes autoinducing peptides (AIPs), cyclic-peptide signaling molecules, to mediate the agr system. Despite the high potency of synthetic AIP analogues in agr inhibition, the potential of AIP molecules as a delivery vehicle for antibacterial agents remains unexplored. Herein, we report that truncated AIP scaffolds can be fused with fluorophore and cytotoxic photosensitizer molecules without compromising their high agr inhibitory activity, binding affinity to the receptor AgrC, or cell specificity. Strikingly, a photosensitizer-AIP conjugate exhibited 16-fold greater efficacy in a S. aureus cell-killing assay than a nontargeting analogue. These findings highlight the potential of truncated AIP conjugates as useful chemical tools for in-depth biological studies and as effective anti-S. aureus agents.
Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston , 1881 East Road, Houston, Texas 77054, United States.
Kyoji
0000-0002-2359-0408
K
Tsuchikama
Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston , 1881 East Road, Houston, Texas 77054, United States.
Yasuhiro
Y
Shimamoto
Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston , 1881 East Road, Houston, Texas 77054, United States.
Yasuaki
Y
Anami
D001426:Bacterial Proteins / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression; D008027:Light; D008826:Microbial Sensitivity Tests; D010456:Peptides, Cyclic / Q000819:agonists / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017319:Photosensitizing Agents / Q000819:agonists / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D053038:Quorum Sensing / Q000187:drug effects* / Q000528:radiation effects; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity / Q000528:radiation effects; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014774:Virulence
C095698:Agr protein, Staphylococcus aureus; C414532:AgrD protein, Staphylococcus; D001426:Bacterial Proteins; D010456:Peptides, Cyclic; D017319:Photosensitizing Agents; D015534:Trans-Activators; D011494:Protein Kinases; C531166:AgrC protein, Staphylococcus
Staphylococcus aureus; autoinducing peptides; conjugation; drug delivery; photodynamic therapy; quorum sensing