Development of Host-Cleavable Antibody-Bactericide Conjugates against Extracellular Pathogens.

Novel antimicrobial agents with potent bactericidal activity are needed to treat infections caused by multidrug-resistant (MDR) extracellular pathogens, such as . Antimicrobial peptides (AMPs) and peptidomimetics are promising alternatives to traditional antibiotics, but their therapeutic use is limited due to the lack of specificity and resulting off-target effects. The incorporation of an antibody into the drug design would alleviate these challenges by localizing the AMP to the target bacterial cells.

Mechanism of Action and Resistance Evasion of an Antimicrobial Oligomer against Multidrug-Resistant Gram-Negative Bacteria.

The last resort for treating multidrug-resistant (MDR) and other MDR Gram-negative bacteria is a class of antibiotics called the polymyxins; however, polymyxin-resistant isolates have emerged. In response, antimicrobial peptides (AMPs) and their synthetic mimetics have been investigated as alternative therapeutic options. Oligothioetheramides (oligoTEAs) are a class of synthetic, sequence-defined oligomers composed of -allylacrylamide monomers and an abiotic dithiol backbone that is resistant to serum degradation.

PEGylated Oligothioetheramide Prodrugs Activated by Host Serum Proteases.

Due to the increasing prominence of antibiotic resistance, novel drug discovery and delivery approaches targeting bacteria are essential. In this work we evaluate a prodrug design to improve the cytotoxic profile of polycationic oligothioetheramides (oligoTEAs), which are promising antimicrobials. Herein we chemically modify the oligoTEA, PDT-4G, with a polyethylene glycol (PEG) and show that 1, 2, and 5 kDa PEGs mitigate cytotoxicity.

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

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.