20.500.12556/RUL-164821 Enhancing antibacterial efficacy combining novel bacterial topoisomerase inhibitors with efflux pump inhibitors and other agents against gram-negative bacteria Background: The novel bacterial topoisomerase inhibitors (NBTIs) developed in our laboratory show potent on-target enzyme inhibition but suffer from low activity against Gram-negative bacteria. Methods: With the aim of improving the antibacterial activity of our compounds against Gram-negative bacteria, we tested them in combination with different efflux pump inhibitors (EPIs), a strategy that showed promise in several other classes of antimicrobials. We also investigated the combined effect of NBTIs with ATP-competitive inhibitors of bacterial type II topoisomerases (ACIs), as well as the antibiofilm properties of our compounds and the combination with EPIs against early and mature Acietobacter baumannii biofilm. Results: Our results demonstrate that combinations of NBTIs with EPI Phenylalanine-arginyl-β-naphthylamide significantly reduce the corresponding NBTIs’ minimal inhibitory concentration values and show potentiation of A. baumannii biofilm inhibition as compared to NBTIs alone. Although combinations of NBITs and ACIs did not show synergistic effects, the FIC index value calculations revealed additive effects for all the combinations of a selected NBTI in combination with three ACIs in all the assayed Gram-negative bacteria from the ESKAPE group. Conclusions: These results show for the first time that combinations of NBTIs with either EPIs or a different class of the topoisomerase inhibitors may be a beneficial strategy to combat difficult-to-treat bacterial infections. topoisomerase inhibitors NBTIs efflux pump inhibitors ESKAPE pathogens antimicrobial resistance bacterial biofilms inhibitorji topoizomeraze NBTI zaviralci iztočne črpalke patogeni ESKAPE protimikrobna odpornost bakterijski biofilmi bakterijska rezistenca true false true Angleški jezik Slovenski jezik Članek v reviji 2024-11-13 11:05:56 2024-11-13 11:06:01 2024-11-22 14:56:16 0000-00-00 00:00:00 2024 0 0 13 str. iss. 11, [article] 1081 Vol. 13 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 579:615.015.8 2079-6382 10.3390/antibiotics13111081 214794499 antibiotics-13-01081.pdf antibiotics-13-01081.pdf 1 7AA729FB2B7A10516F6F761D26CF3BB9 bc0dd2bc11f7e110773ea653f9076c5d828f823f011a8087eb994fdb4f8c4cd6 cea33662-a1a6-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=195561 https://www.mdpi.com/2079-6382/13/11/1081 1 865f2f84-a1a6-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=195559 Fakulteta za farmacijo Veterinarska fakulteta 0 0 0