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

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

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.

• Language: English
• Keywords: bacteria, genetics, inhibitors, organic acids, peptides, proteins
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: Str. 24387-24395
• Numbering: Vol. 8, iss. 27
• PID: 20.500.12556/RUL-152634
• UDC: 579.8:615.2
• ISSN on article: 2470-1343
• DOI: 10.1021/acsomega.3c01930
• COBISS.SI-ID: 157232131
• Publication date in RUL: 01.12.2023

Record is a part of a journal

• Title: ACS omega
• Shortened title: ACS omega
• Publisher: American Chemical Society
• ISSN: 2470-1343
• COBISS.SI-ID: 525873945

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