Synthesis and biological evaluation of novel carbazole derivatives as broad-spectrum antibacterial agents to fight antimicrobial resistance (AMR)

The escalation of antimicrobial resistance, especially among ESKAPE pathogens, calls for new antibacterial agents with improved effectiveness against bacteria often causing difficult-to-treat infections. In this work, two sets of carbazole derivatives were designed and evaluated against a broad panel of both reference strains and resistant clinical isolates. In the first set, chlorinated compounds showed superior antibacterial performance compared with non-halogenated analogues. The addition of cationic or chelating functionalities (e.g., 4e, 4f, 6b, and 7b) further increased activity against Gram-negative species even without colistin, suggesting improved interaction with or penetration through the outer membrane. Compounds 6b and 7b were particularly effective against multidrug-resistant isolates, with no apparent cross-resistance. The second set did not display a clear dependence on halogen substitution; however, piperazino-substituted derivatives (23a-d) showed selective activity against Gram-positive bacteria and resistant isolates, which was strongly enhanced, on Gram-negatives, by subinhibitory concentrations of colistin. A three-parameter physicochemical analysis integrating lipophilicity, polar surface area, and dipole moment distinguished active from inactive molecules and implicated membrane disruption as the underlying mechanism, a finding further supported by propidium iodide uptake experiments. Overall, carbazole derivatives represent promising candidates for the development of new antibacterial agents targeting resistant pathogens.