Inhibition\nof Pseudomonas aeruginosa Carbonic\nAnhydrases, Exploring Ciprofloxacin Functionalization Toward\nNew Antibacterial Agents: An In-Depth Multidisciplinary Study

Ciprofloxacin (CPX) is one of the most employed antibiotics\nin\nclinics to date. However, the rise of drug-resistant bacteria is dramatically\nimpairing its efficacy, especially against life-threatening pathogens,\nsuch as Pseudomonas aeruginosa. This\nGram-negative bacterium is an opportunistic pathogen, often infecting\nimmuno-compromised patients with severe or fatal outcomes. The evidence\nof the possibility of exploiting Carbonic Anhydrase (CA, EC: 4.2.1.1)\nenzymes as pharmacological targets along with their role in P. aeruginosa virulence inspired the derivatization\nof CPX with peculiar CA-inhibiting chemotypes. Thus, a large library\nof CPX derivatives was synthesized and tested on a panel of bacterial\nCAs and human isoenzymes I and II. Selected derivatives were evaluated\nfor antibacterial activity, revealing bactericidal and antibiofilm\nproperties for some compounds. Importantly, promising preliminary\nabsorption, distribution, metabolism, and excretion (ADME) properties <i>in vitro</i> were found and no cytotoxicity was detected for\nsome representative compounds when tested in Galleria\nmellonella larvae.