Macrocyclic Peptides: Novel Antibiotic Treatment against Staphylococcus Aureus

Web Published:

12/10/2020

Description:

Macrocyclic Peptides : Novel antibiotic treatment against Staphyloccocus aureus

Princeton Docket # 20-3668

Researchers at Princeton University and University of Tokyo have combined mRNA display technology with lipid-nanodisc based selections to identify high affinity ligands of the integral membrane sensor domain of the histidine kinase, AgrC. In S. aureus, virulence gene expression is under the control of the accessory gene regulator (agr) quorum sensing system. Within the agr circuit, AgrC, senses the quorum signal and is critical to the regulation of virulence. QQs are molecules that can bind to the integral membrane sensor domain of AgrC and are potent inhibitors of S. aureus virulence in vitro and in vivo. The QQs are not only potent inhibitors, but by replacing thiolactone with thioether linkages the macrocycle is less prone to hydrolysis, a common decomposition pattern in similar inhibitors.

Antibiotic resistant bacterial infections represent a major public health challenge. Each increase in resistance requires improving treatments and the need for novel pharmaceuticals. Anti-virulence strategies have been proposed where therapeutic agents are administered to interfere with production of virulence factors rather than directly killing the bacterium. This approach is considered advantageous due to its low selection pressure for resistance build-up and minimal perturbation of the host microbiota. The Quorum Quenchers (QQ) are a collection of macrocyclic peptides which are potent inhibitors of Staphylococcus aureus virulence.

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