Exploring the 5-substituted 2-aminobenzothiazole-based DNA gyrase B inhibitors active against ESKAPE pathogens

Sterle, Maša (avtor), Durcik, Martina (avtor), Kikelj, Danijel (avtor), Zidar, Nace (avtor), Peterlin-Mašič, Lucija (avtor), Ilaš, Janez (avtor), Tomašič, Tihomir (avtor), Cotman, Andrej Emanuel (avtor), Zega, Anamarija (avtor)

We present a new series of 2-aminobenzothiazole-based DNA gyrase B inhibitors with promising activity against ESKAPE bacterial pathogens. Based on the binding information extracted from the cocrystal structure of DNA gyrase B inhibitor A, in complex with Escherichia coli GyrB24, we expanded the chemical space of the benzothiazole-based series to the C5 position of the benzothiazole ring. In particular, compound E showed low nanomolar inhibition of DNA gyrase (IC$_{50}$ < 10 nM) and broad-spectrum antibacterial activity against pathogens belonging to the ESKAPE group, with the minimum inhibitory concentration < 0.03 μg/mL for most Gram-positive strains and 4–16 μg/mL against Gram-negative E. coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. To understand the binding mode of the synthesized inhibitors, a combination of docking calculations, molecular dynamics (MD) simulations, and MD-derived structure-based pharmacophore modeling was performed. The computational analysis has revealed that the substitution at position C5 can be used to modify the physicochemical properties and antibacterial spectrum and enhance the inhibitory potency of the compounds. Additionally, a discussion of challenges associated with the synthesis of 5-substituted 2-aminobenzothiazoles is presented.

• Jezik: Angleški jezik
• Ključne besede: bacteria, genetics, inhibitors, organic acids, peptides, proteins
• 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: 2023
• Št. strani: Str. 24387-24395
• Številčenje: Vol. 8, iss. 27
• PID: 20.500.12556/RUL-152634
• UDK: 579.8:615.2
• ISSN pri članku: 2470-1343
• DOI: 10.1021/acsomega.3c01930
• COBISS.SI-ID: 157232131
• Datum objave v RUL: 01.12.2023

Gradivo je del revije

• Naslov: ACS omega
• Skrajšan naslov: ACS omega
• Založnik: American Chemical Society
• ISSN: 2470-1343
• COBISS.SI-ID: 525873945

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: inhibitorji, organske kisline, proteini, bakterije, genetika, peptidi