Bourgard Catarina, Rodríguez-Hernández Diego, Rudenko Anastasia, Rutgersson Carolin, Palm Martin, Larsson D G Joakim, Farewell Anne, Grøtli Morten, Sunnerhagen Per
Department of Chemistry and Molecular Biology, University of Gothenburg, S-405 30 Gothenburg, Sweden.
Centre for Antibiotic Resistance Research (CARe), University of Gothenburg, S-405 30 Gothenburg, Sweden.
Antibiotics (Basel). 2022 Aug 17;11(8):1115. doi: 10.3390/antibiotics11081115.
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 (EC 2-20 µM) against antibiotic-resistant isolates of the Gram-negative members of the ESKAPE group (, , , spp.) and 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 collections with known susceptibility patterns against established antibiotics indicates that it is distinct from lactam and quinolone antibiotics.
细菌中的抗生素耐药性是一个日益严峻的全球挑战。造成这一情况的主要原因是在开发对革兰氏阴性菌有效的新型抗生素方面进展有限。在此，我们研究了一种最初作为抗锥虫药开发的双阳离子双胍基芳基呋喃及其新衍生物的抗菌活性。这些化合物对ESKAPE组革兰氏阴性菌的耐药菌株（、、、菌属）以及具有不同抗生素敏感性模式的菌，包括产超广谱β-内酰胺酶（ESBL）菌株，均表现出良好的活性（最低抑菌浓度为2 - 20 μM）。细胞毒性适中，并且几种新衍生物的细胞毒性低于先导分子，具有更好的选择性指数（对几种ESKAPE菌株而言为40 - 80）。这些分子抗菌活性的分子机制尚不清楚，但针对人类ESKAPE菌株以及对已确立抗生素具有已知敏感性模式的菌库进行的敏感性分析表明，其机制与β-内酰胺类和喹诺酮类抗生素不同。
