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Rational design of balanced dual-targeting antibiotics with limited resistance [Elektronski vir]Nyerges, Ákos ...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.Source: PLoS biology [Elektronski vir]. - ISSN 1545-7885 (Vol. 18, iss. 10, 2020, str. 1-31)Type of material - e-articlePublish date - 2020Language - englishCOBISS.SI-ID - 31342595
Author
Nyerges, Ákos |
Tomašič, Tihomir |
Durcik, Martina |
Revesz, T. |
Szili, Petra |
Skok, Žiga, farmacevt |
Zidar, Nace |
Ilaš, Janez |
Zega, Anamarija |
Kikelj, Danijel |
Peterlin-Mašič, Lucija
Topics
Antibiotiki |
Farmacevtska kemija
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Author | Nyerges, Ákos ... |
Title | Rational design of balanced dual-targeting antibiotics with limited resistance [Elektronski vir] |
Publication date | 2020-10-05 |
COBISS.SI-ID | 31342595 |
Publication version in repository | Publisher's version |
Publication licence | Creative Commons Attribution 4.0 International |
Embargo | Immediate publication for public |
Project(s) from which the publication was funded
Title | Acronym | Project ID | Funder |
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Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin | P1-0208-2015 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
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Nove protitumorne učinovine napetostno odvisnih kalijevih kanalov hEag1 in njihova validacija v limfomih | J1-9192-2018 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
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Establishing the Hungarian Center of Excellence for Molecular Medicine in partnership with EMBL | HCEMM | 739593 |
European Commission |
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DRS, in which the journal is indexed
Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Nyerges, Ákos | ![]() |
Tomašič, Tihomir | 28334 |
Durcik, Martina | 50490 |
Revesz, T. | ![]() |
Szili, Petra | ![]() |
Skok, Žiga, farmacevt | 39202 |
Zidar, Nace | 28905 |
Ilaš, Janez | 24400 |
Zega, Anamarija | 18633 |
Kikelj, Danijel | 01463 |
Peterlin-Mašič, Lucija | 19317 |
Source: Personal bibliographies
and: SICRIS
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