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 Pseudomonas aeruginosa. 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. Antibody-drug conjugates (ADCs) have already achieved clinical success as anticancer therapeutics, due to the ability of the antibody to deliver the payload directly to the cancer cells. This strategy involves the selective delivery of highly cytotoxic drugs to the target cells, which enables a broad therapeutic window. This platform can be translated to the treatment of infections, whereby an antibody is used to deliver an antimicrobial agent to the bacterial antigen. Herein, we propose the development of an antibody-bactericide conjugate (ABC) in which the antibacterial oligothioetheramide (oligoTEA), BDT-4G, is coupled to an anti-P. aeruginosa antibody via a cleavable linker. The drug BDT-4G was chosen based on its efficacy against a range of P. aeruginosa isolates and its ability to evade mechanisms conferring resistance to the last-resort agent polymyxin B. We demonstrate that the ABC binds to the bacterial cell surface, and following cleavage of the peptide linker, the oligoTEA payload is released and exhibits antipseudomonal activity.