Inhibition of <i>Pseudomonas aeruginosa</i> Carbonic Anhydrases, Exploring Ciprofloxacin Functionalization Toward New Antibacterial Agents: An In-Depth Multidisciplinary Study

Abstract

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