P. aeruginosa is a versatile pathogen, living in breathing machines, on catheters and spreading by touch. It is a major source of hospital-acquired infections worldwide, causing morbidity in patients with chronic infections, wounds or burns. Like many Gram-negative pathogens, P. aeruginosa is difficult to treat due to multiple mechanisms of drug resistance, including enzymes to break down drugs and efflux pumps to remove internalized drugs. In resistant strains, first-line antibiotics are less likely to be successful and physicians are forced to resort to last-line antimicrobial agents to treat bacterial infections. Fluoroquinolones, such as ciprofloxacin, represent a major drug class for the treatment of P. aeruginosa and other bacterial infections, yet have recently been relegated by the FDA to last-resort drugs due to drug-induced tendinopathy, nephrotoxicity, and other serious adverse effects. Resistance to most small molecule antibiotics has been observed with the highest rates of resistance to fluoroquinolones. The majority of small-molecule antibiotics in development are categorized in established drug classes and thus suffer from similar resistance mechanisms. As such, large biomolecules such as antibodies are being explored as emerging therapies. With a unique mechanism of action compared to small-molecule antibiotics, antibodies are promising candidates for adjunctive therapy. We posit that an antibiotic-bearing antibody drug conjugate (ADC) can be utilized to target multiple mechanisms of bacterial cell death along with delivering the bactericidal agent directly to the site of action to minimize undesired off-target effects. One ADC has been recently investigated to target S. aureus for opsonization and killing in human macrophages. Binding of the antibody to bacteria triggers internalization of the antibody-bacteria complex into the lysosomes of macrophages where an antibiotic is released by a cathepsin-cleavable linker. By this mechanism, the ADC is able to eliminate intracellular S. aureus populations. Our work focuses on the design and evaluation of a full IgG antibody that is amenable to bioconjugation for use as an ADC in the potentiation of small molecule antibiotics in the treatment of P. aeruginosa infections.

Antibody drug conjugates as enhanced therapeutics against the drug resistant bacteria Pseudomonas aeruginosa

2019 Fall National Meeting

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