20.500.12556/RUL-141942 Rational design of balanced dual-targeting antibiotics with limited resistance Antibiotics that inhibit multiple bacterial targets offer a promising therapeutic strategy against resistance evolution, but developing such antibiotics is challenging. Here we demonstrate that a rational design of balanced multitargeting antibiotics is feasible by using a medicinal chemistry workflow. The resultant lead compounds, ULD1 and ULD2, belonging to a novel chemical class, almost equipotently inhibit bacterial DNA gyrase and topoisomerase IV complexes and interact with multiple evolutionary conserved amino acids in the ATP-binding pockets of their target proteins. ULD1 and ULD2 are excellently potent against a broad range of gram-positive bacteria. Notably, the efficacy of these compounds was tested against a broad panel of multidrug-resistant Staphylococcus aureus clinical strains. Antibiotics with clinical relevance against staphylococcal infections fail to inhibit a significant fraction of these isolates, whereas both ULD1 and ULD2 inhibit all of them (minimum inhibitory concentration [MIC] +-1 [micro]g/mL). Resistance mutations against these compounds are rare, have limited impact on compound susceptibility, and substantially reduce bacterial growth. Based on their efficacy and lack of toxicity demonstrated in murine infection models, these compounds could translate into new therapies against multidrug-resistant bacterial infections. antibiotics bacterial resistance bacterial targets antibiotiki farmacevtska kemija true false true Angleški jezik Slovenski jezik Članek v reviji 2022-10-12 08:41:59 2022-10-12 08:42:03 2022-10-13 04:03:52 0000-00-00 00:00:00 2020 0 0 Str. 1-31 iss. 10 Vol. 18 2020 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54:615.33 1545-7885 10.1371/journal.pbio.3000819 31342595 file.pdf file.pdf 1 8635951289FE951C6B89CB716C918D0C b8bc15942a1197c83c200de36586bc0e06ef37504abc668339211f1c84c1bddc 49c297b9-49fa-11ed-9c94-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=163144 https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000819 1 f1f2f754-49f8-11ed-9c94-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=163142 Fakulteta za farmacijo 0 0 0