Empowering Antibiotics In The Amr Landscape: Insights From Dendrimer Conjugation In Ali Systems

In the shadow of the AMR crisis, reigniting the antibiotic pipeline has emerged as a pivotal strategy. Despite the urgent need, there has been a decrease in finding new types of natural or synthetic antibiotics over the past forty years. Of the 65 antibiotics introduced in the last two decades, only four were genuinely new pharmacological classes, whilst the remainder were merely derivatives or modifications of pre-existing compounds. This challenge arises from the need to bypass bacterial resistance, which, paradoxically, is also the target.

Inspired by a 2006 study that successfully integrated propranolol with a known drug delivery polymer, DAB-PAMAM dendrimer, for enhanced cellular uptake, we advanced this approach by conjugating the antibiotic ciprofloxacin with PAMAM dendrimers. This strategy aims to enhance the antibiotic’s effectiveness by preventing its ejection from cells.

The screening results were promising as Escherichia coli showed MIC values of 1.25 µg/µl and Pseudomonas aeruginosa 1-2 µg/µl. Staphylococcus aureus exhibited values, oscillating between 2-4 µg/µl. MIC values, which lowered by a factor of 2 when tested in media other than MHB. The compounds did not result in cytotoxicity nor hemolysis.

An important outcome of these experiments was the insight that tackling AMR requires not only identification of suitable candidates, but also require that standardized screening methodologies are in congruence with clinical needs. Therefore, we employed an air-liquid interface (ALI) culture set-up to mimic respiratory epithelial cells’ natural environment. By introducing P. aeruginosa, a severe cause of respiratory infections, we sought to compare its behavior with standard lab screenings, aiming to bridge the gap between conventional lab methods and clinical needs inside the antimicrobial development pipeline.