|Title||Design of a PEGylated Antimicrobial Prodrug with Species-Specific Activation.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||O'Leary MK, Chen SS, Westblade LF, Alabi CA|
|Date Published||2021 02 08|
|Keywords||Anti-Bacterial Agents, Anti-Infective Agents, Antimicrobial Cationic Peptides, Microbial Sensitivity Tests, Polyethylene Glycols, Prodrugs, Pseudomonas aeruginosa, Species Specificity|
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.
|PubMed Central ID||PMC8270352|
|Grant List||R21 AI154102 / AI / NIAID NIH HHS / United States |
S10 OD017992 / OD / NIH HHS / United States
Lars Westblade, Ph.D.