Rational design of balanced dual-targeting antibiotics with limited resistance.

• Main Authors: Akos Nyerges, Tihomir Tomašič, Martina Durcik, Tamas Revesz, Petra Szili, Gabor Draskovits, Ferenc Bogar, Žiga Skok, Nace Zidar, Janez Ilaš, Anamarija Zega, Danijel Kikelj, Lejla Daruka, Balint Kintses, Balint Vasarhelyi, Imre Foldesi, Diána Kata, Martin Welin, Raymond Kimbung, Dorota Focht, Lucija Peterlin Mašič, Csaba Pal
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2020-10-01
• Series: PLoS Biology
• Online Access: https://doi.org/10.1371/journal.pbio.3000819

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 μg/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.