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Dual Escherichia coli DNA Gyrase A and B Inhibitors with Antibacterial Activity
Author(s) -
Fois Benedetta,
Skok Žiga,
Tomašič Tihomir,
Ilaš Janez,
Zidar Nace,
Zega Anamarija,
Peterlin Mašič Lucija,
Szili Petra,
Draskovits Gábor,
Nyerges Ákos,
Pál Csaba,
Kikelj Danijel
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900607
Subject(s) - dna gyrase , dna supercoil , escherichia coli , novobiocin , microbiology and biotechnology , antibacterial activity , biology , ciprofloxacin , antibacterial agent , bacteria , dna , topoisomerase iv , antibiotics , biochemistry , genetics , dna replication , gene
The emergence of multidrug‐resistant bacteria is a global health threat necessitating the discovery of new antibacterials and novel strategies for fighting bacterial infections. We report first‐in‐class DNA gyrase B (GyrB) inhibitor/ciprofloxacin hybrids that display antibacterial activity against Escherichia coli . Whereas DNA gyrase ATPase inhibition experiments, DNA gyrase supercoiling assays, and in vitro antibacterial assays suggest binding of the hybrids to the E. coli GyrA and GyrB subunits, an interaction with the GyrA fluoroquinolone‐binding site seems to be solely responsible for their antibacterial activity. Our results provide a foundation for a new concept of facilitating entry of nonpermeating GyrB inhibitors into bacteria by conjugation with ciprofloxacin, a highly permeable GyrA inhibitor. A hybrid molecule containing GyrA and GyrB inhibitor parts entering the bacterial cell would then elicit a strong antibacterial effect by inhibition of both the GyrA and GyrB subunits of DNA gyrase and potentially slow bacterial resistance development.