Rational design of balanced dual-targeting antibiotics with limited resistance

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

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.

• Jezik: Angleški jezik
• Ključne besede: antibiotics, bacterial resistance, bacterial targets
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2020
• Št. strani: Str. 1-31
• Številčenje: Vol. 18, iss. 10
• PID: 20.500.12556/RUL-141942
• UDK: 615.4:54:615.33
• ISSN pri članku: 1545-7885
• DOI: 10.1371/journal.pbio.3000819
• COBISS.SI-ID: 31342595
• Datum objave v RUL: 12.10.2022

Gradivo je del revije

• Naslov: PLoS biology
• Skrajšan naslov: PLoS biol.
• Založnik: PLOS
• ISSN: 1545-7885
• COBISS.SI-ID: 2943764

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: antibiotiki, farmacevtska kemija