Rational Design of Dipicolylamine-Containing Carbazole Amphiphiles Combined with Zn²⁺ as Potent Broad-Spectrum Antibacterial Agents with a Membrane-Disruptive Mechanism

Abstract

Antibiotic resistance has become one of the most urgently important problems facing healthcare providers. A novel series of dipicolylamine-containing carbazole amphiphiles with strong Zn 2+ chelating ability were synthesized, biomimicking cationic antimicrobial peptides. Effective broad-spectrum 16 combined with 12.5 μg/mL Zn 2+ was identified as the most promising antimicrobial candidate. 16 combined with 12.5 μg/mL Zn 2+ exhibited excellent antimicrobial activity against both Grampositive and Gram-negative bacteria (MICs = 0.78−3.125 μg/mL), weak hemolytic activity, and low cytotoxicity. Time-kill kinetics and mechanism studies revealed 16 combined with 12.5 μg/mL Zn 2+ had rapid bacterial killing properties, as evidenced by disruption of the integrity of bacterial cell membranes, effectively preventing bacterial resistance development. Importantly, 16 combined with 12.5 μg/mL Zn 2+ showed excellent in vivo efficacy in a murine keratitis model caused by Staphylococcus aureus ATCC29213 or Pseudomonas aeruginosa ATCC9027. Therefore, 16 combined with 12.5 μg/mL Zn 2+ could be a promising candidate for treating bacterial infections.

Unique Carbazole-Oxadiazole Derivatives as New Potential Antibiotics for Combating Gram-Positive and -Negative Bacteria

“…To further investigate the preliminary antibacterial mechanisms of this series of active compounds, the inner-membrane permeabilities of MRSA and P. aeruginosa ATCC 27853 assays were determined in the presence of carbazole-oxadiazoles 5g , 5i , and carbazole-tetrazoles 23b – c using the fluorescence probes propidium iodide (PI) and calcein-AM, in which PI only stained the damaged cells while calcein-AM made living cells fluoresce green. , A dose-dependent increase of PI fluorescence intensity in MRSA was observed in Figure , which manifested that carbazole-oxadiazoles 5g and 5i could increase the permeability of MRSA membrane. A similar phenomenon was also detected both in 23b - and 23c -treated P.…”

Natural Berberine-derived Azolyl Ethanols as New Structural Antibacterial Agents against Drug-Resistant Escherichia coli

“…Efficient bactericidal activity is one of the most properties for an effective antibacterial agent. , Time-kill kinetic assays were carried out to evaluate the bactericidal performance of berberine derivatives. E.…”

The synthesis and antibacterial activity study of ruthenium-based metallodrugs with a membrane-disruptive mechanism against Staphylococcus aureus

“…The bactericidal rates of four complexes (Ru2, Ru3, Ru13 and Ru14) were investigated through time-kill kinetics assay. 30,31 As can be seen in Fig. 4, complexes Ru2, Ru3 and Ru13 killed ≥99.9% of S. aureus at 8 × MIC within 1 hour, since no viable bacteria were observed.…”