Design of a PEGylated Antimicrobial Prodrug with Species-Specific Activation

Overview

Journal Biomacromolecules

Publisher American Chemical Society

Specialties Biochemistry
Biology
Molecular Biology

Date 2021 Jan 11

PMID 33428376

Citations 2

Authors

Meghan K OLeary

Sabrina S Chen

Lars F Westblade

Christopher A Alabi

Affiliations

Soon will be listed here.

Abstract

The rise of multidrug-resistant (MDR) "superbugs" has created an urgent need to develop new classes of antimicrobial agents to target these organisms. Oligothioetheramides (oligoTEAs) are a unique class of antimicrobial peptide (AMP) mimetics with one promising compound, BDT-4G, displaying potent activity against MDR clinical isolates. Despite widely demonstrated potency, BDT-4G and other AMP mimetics have yet to enjoy broad preclinical success against systemic infections, primarily due to their cytotoxicity. In this work, we explore a prodrug strategy to render BDT-4G inactive until it is exposed to an enzyme secreted by the targeted bacteria. The prodrug consists of polyethylene glycol (PEG) conjugated to BDT-4G by a peptide substrate. PEG serves to inactivate and reduce the toxicity of BDT-4G by masking its cationic charge and antimicrobial activity is recovered following site-specific cleavage of the short peptide linker by LasA, a virulence factor secreted by . This approach concurrently reduces cytotoxicity by greater than 1 order of magnitude and provides species specificity through the identity of the cleavable linker.

Citing Articles

Lectin-Targeted Prodrugs Activated by for Self-Destructive Antibiotic Release.

Meiers J, Rox K, Titz A J Med Chem. 2022; 65(20):13988-14014.

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Peptide/β-Peptoid Hybrids with Ultrashort PEG-Like Moieties: Effects on Hydrophobicity, Antibacterial Activity and Hemolytic Properties.

Frederiksen N, Louka S, Mudaliar C, Domraceva I, Kreicberga A, Pugovics O Int J Mol Sci. 2021; 22(13).

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