Rational design of balanced dual-targeting antibiotics with limited resistance

PLoS Biol. 2020 Oct 5;18(10):e3000819. doi: 10.1371/journal.pbio.3000819. eCollection 2020 Oct.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / therapeutic use
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Directed Molecular Evolution
  • Disease Models, Animal
  • Drug Design*
  • Drug Resistance, Multiple, Bacterial / drug effects*
  • Enzyme Inhibitors / pharmacology
  • Hep G2 Cells
  • Humans
  • Hydrogen-Ion Concentration
  • MCF-7 Cells
  • Microbial Sensitivity Tests
  • Mutation / genetics
  • Skin / drug effects
  • Skin / microbiology
  • Staphylococcal Infections / drug therapy
  • Staphylococcus aureus / drug effects
  • Toxicity Tests

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Enzyme Inhibitors

Grant support

The study was supported by the following research grants: European Research Council H2020-ERC-2014-CoG 648364–Resistance Evolution (CP) (https://erc.europa.eu/); ‘Célzott Lendület’ Programme of the Hungarian Academy of Sciences LP-2017–10/2017 (CP) (https://mta.hu/english); ‘Élvonal’ KKP 126506 (CP) (https://nkfih.gov.hu/english-nkfih), GINOP-2.3.2–15–2016–00014 (EVOMER, for CP), GINOP-2.3.2–15–2016–00020 (MolMedEx TUMORDNS) and GINOP-2.3.3–15–2016–00001 (https://www.palyazat.gov.hu/program_szechenyi_2020), EFOP 3.6.3-VEKOP-16-2017-00009 (PSz, TR) (https://u-szeged.hu/fejlesztesiprojektek), UNKP-19-3 New National Excellence Program of the Ministry for Innovation and Technology (PSz) (http://www.unkp.gov.hu/unkp-rol), the European Union’s Horizon 2020 research and innovation programme under grant agreement No 739593 (BK) (https://ec.europa.eu/programmes/horizon2020/en), and a PhD fellowship from the Boehringer Ingelheim Fonds (AN) (https://www.boehringer-ingelheim.com/procurement/research-development/boehringer-ingelheim-fonds). The work was also funded by the Slovenian Research Agency (Grant No. P1-0208 and J1-9192) (https://www.arrs.si/en/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.