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

Rational design of balanced dual-targeting antibiotics with limited resistance

  • PLoS Biol. 2020 Oct 5;18(10):e3000819. doi: 10.1371/journal.pbio.3000819.
Akos Nyerges 1,  Tihomir Tomašič 2,  Martina Durcik 2,  Tamas Revesz 1 3,  Petra Szili 1 4,  Gabor Draskovits 1,  Ferenc Bogar 5,  Žiga Skok 2,  Nace Zidar 2,  Janez Ilaš 2,  Anamarija Zega 2,  Danijel Kikelj 2,  Lejla Daruka 1 6,  Balint Kintses 1 7,  Balint Vasarhelyi 1,  Imre Foldesi 8,  Diána Kata 8,  Martin Welin 9,  Raymond Kimbung 9,  Dorota Focht 9,  Lucija Peterlin Mašič 2,  Csaba Pal 1
Affiliations

Affiliations

  • 1 Synthetic and Systems Biology Unit, Biological Research Center, Szeged, Hungary.
  • 2 University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
  • 3 Doctoral School of Theoretical Medicine, University of Szeged, Szeged, Hungary.
  • 4 Doctoral School of Multidisciplinary Medical Sciences, University of Szeged, Szeged, Hungary.
  • 5 MTA-SZTE Biomimetic Systems Research Group, Department of Medical Chemistry, University of Szeged, Hungary.
  • 6 Doctoral School of Biology, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary.
  • 7 HCEMM-BRC Translational Microbiology Lab, Szeged, Hungary.
  • 8 Department of Laboratory Medicine, University of Szeged, Szeged, Hungary.
  • 9 SARomics Biostructures, Medicon Village, Lund, Sweden.
PMID: 33017402 DOI: 10.1371/journal.pbio.3000819
Abstract

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.

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