Poly(2-oxazoline)-Antibiotic Conjugates with Penicillins.

Area of Science:

• Polymer Chemistry
• Medicinal Chemistry
• Microbiology

Background:

• Antibiotic resistance necessitates novel drug delivery systems.
• Polymer-antibiotic conjugates are an under-explored area compared to small-molecule derivatization.
• Poly(2-oxazoline)s (POx) offer water solubility and tunable properties for drug conjugation.

Purpose of the Study:

• To synthesize and characterize novel penicillin G (PenG) and penicillin V (PenV) conjugates with poly(2-oxazoline)s (POx).
• To evaluate the stability and antimicrobial activity of these conjugates, particularly against penicillinase.
• To investigate the impact of an additional antimicrobial dodecyltrimethylammonium group (DDA-X) on conjugate efficacy.

Main Methods:

• Conjugation of PenG and PenV to POx end groups via their carboxylic acid function, forming ester linkages.
• Hydrolysis stability assays to compare conjugates with free penicillins and assess β-lactam ring stability.
• Antimicrobial activity testing against Staphylococcus aureus and Escherichia coli, with and without penicillinase.

Main Results:

• Ester linkages in POx-penicillin conjugates demonstrated greater stability against hydrolysis than the native penicillin β-lactam ring.
• Conjugates showed up to 20-fold increased stability against penicillinase-catalyzed hydrolysis.
• Antibiotic activity against S. aureus in the presence of penicillinase was enhanced up to 350-fold compared to free penicillins.
• Conjugates incorporating a DDA-X group exhibited superior activity, comparable to or exceeding penicillinase-stable cloxacillin.

Conclusions:

• Polymer conjugation of penicillins via stable ester linkages offers a promising strategy to overcome β-lactam instability and penicillinase activity.
• The developed POx-penicillin conjugates retain antimicrobial efficacy and show significantly improved performance in enzymatic degradation environments.
• Dual-functionalized conjugates (POx-DDA-X-PenG/V) represent a potent new class of antibiotics effective against resistant bacteria.