Rational design of balanced dual-targeting antibiotics with limited resistance

Nyerges, Ákos (author), Tomašič, Tihomir (author), Durcik, Martina (author), Revesz, T. (author), Szili, Petra (author), Skok, Žiga (author), Zidar, Nace (author), Ilaš, Janez (author), Zega, Anamarija (author), Kikelj, Danijel (author), Peterlin-Mašič, Lucija (author)

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.

• Language: English
• Keywords: antibiotics, bacterial resistance, bacterial targets
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2020
• Number of pages: Str. 1-31
• Numbering: Vol. 18, iss. 10
• PID: 20.500.12556/RUL-141942
• UDC: 615.4:54:615.33
• ISSN on article: 1545-7885
• DOI: 10.1371/journal.pbio.3000819
• COBISS.SI-ID: 31342595
• Publication date in RUL: 12.10.2022

Record is a part of a journal

• Title: PLoS biology
• Shortened title: PLoS biol.
• Publisher: PLOS
• ISSN: 1545-7885
• COBISS.SI-ID: 2943764

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: antibiotiki, farmacevtska kemija