Development of Dicationic Bisguanidine-Arylfuran Derivatives as Potent Agents against Gram-Negative Bacteria

• Main Authors: Catarina Bourgard (Author), Diego Rodríguez-Hernández (Author), Anastasia Rudenko (Author), Carolin Rutgersson (Author), Martin Palm (Author), D. G. Joakim Larsson (Author), Anne Farewell (Author), Morten Grøtli (Author), Per Sunnerhagen (Author)
• Format: Book
• Published: MDPI AG, 2022-08-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Antibiotic resistance among bacteria is a growing global challenge. A major reason for this is the limited progress in developing new classes of antibiotics active against Gram-negative bacteria. Here, we investigate the antibacterial activity of a dicationic bisguanidine-arylfuran, originally developed as an antitrypanosomal agent, and new derivatives thereof. The compounds showed good activity (EC₅₀ 2-20 µM) against antibiotic-resistant isolates of the Gram-negative members of the ESKAPE group (<i>Klebsiella pneumoniae</i>, <i>Acinetobacter baumannii</i>, <i>Pseudomonas aeruginosa</i>, <i>Enterobacter</i> spp.) and <i>Escherichia coli</i> with different antibiotic susceptibility patterns, including ESBL isolates. Cytotoxicity was moderate, and several of the new derivatives were less cytotoxic than the lead molecule, offering better selectivity indices (40-80 for several ESKAPE isolates). The molecular mechanism for the antibacterial activity of these molecules is unknown, but sensitivity profiling against human ESKAPE isolates and <i>E. coli</i> collections with known susceptibility patterns against established antibiotics indicates that it is distinct from lactam and quinolone antibiotics.

Item Description

10.3390/antibiotics11081115
2079-6382