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

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 Pseudomonas aeruginosa. 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 P. aeruginosa 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 in vitro were found and no cytotoxicity was detected for
some representative compounds when tested in Galleria
mellonella larvae.