Design of a PEGylated Antimicrobial Prodrug with Species-Specific Activation.

TitleDesign of a PEGylated Antimicrobial Prodrug with Species-Specific Activation.
Publication TypeJournal Article
Year of Publication2021
AuthorsO'Leary MK, Chen SS, Westblade LF, Alabi CA
JournalBiomacromolecules
Volume22
Issue2
Pagination984-992
Date Published2021 02 08
ISSN1526-4602
KeywordsAnti-Bacterial Agents, Anti-Infective Agents, Antimicrobial Cationic Peptides, Microbial Sensitivity Tests, Polyethylene Glycols, Prodrugs, Pseudomonas aeruginosa, Species Specificity
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.

DOI10.1021/acs.biomac.0c01695
Alternate JournalBiomacromolecules
PubMed ID33428376
PubMed Central IDPMC8270352
Grant ListR21 AI154102 / AI / NIAID NIH HHS / United States
S10 OD017992 / OD / NIH HHS / United States
Related Faculty: 
Lars Westblade, Ph.D.

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