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Development of benzimidazole-based derivatives as antimicrobial agents and their synergistic effect with colistin against gram-negative bacteria

Gram-negative bacteria pose a distinctive risk worldwide, especially with the evolution of major resistance to carbapenems, fluoroquinolones and colistin. Therefore, development of new antibacterial agents to target Gram-negative infections is of utmost importance. Using phenotypic screening, we syn...

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Hauptverfasser: Dokla, Eman M. E. (VerfasserIn) , Abutaleb, Nader S. (VerfasserIn) , Milik, Sandra N. (VerfasserIn) , Li, Daoyi (VerfasserIn) , El-Baz, Karim (VerfasserIn) , Shalaby, Menna-Allah W. (VerfasserIn) , Al-Karaki, Rawan (VerfasserIn) , Nasr, Maha (VerfasserIn) , Klein, Christian D. (VerfasserIn) , Abouzid, Khaled A. M. (VerfasserIn) , Seleem, Mohamed N. (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: [15 January 2020]
In: European journal of medicinal chemistry
Year: 2019, Jahrgang: 186
ISSN:1768-3254
DOI:10.1016/j.ejmech.2019.111850
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ejmech.2019.111850
Verlag, lizenzpflichtig, Volltext: http://www.sciencedirect.com/science/article/pii/S0223523419310025
Volltext
Verfasserangaben:Eman M. E. Dokla, Nader S. Abutaleb, Sandra N. Milik, Daoyi Li, Karim El-Baz, Menna-Allah W. Shalaby, Rawan Al-Karaki, Maha Nasr, Christian D. Klein, Khaled A. M. Abouzid, Mohamed N. Seleem
Beschreibung
Zusammenfassung:Gram-negative bacteria pose a distinctive risk worldwide, especially with the evolution of major resistance to carbapenems, fluoroquinolones and colistin. Therefore, development of new antibacterial agents to target Gram-negative infections is of utmost importance. Using phenotypic screening, we synthesized and tested thirty-one benzimidazole derivatives against E. coli JW55031 (TolC mutant strain). Compound 6c showed potent activity with MIC value of 2μg/ml, however, it lacked activity against several Gram-negative microbes with intact efflux systems, including E. coli BW25113 (wild-type strain). Combination of 6c with colistin partially restored its antibacterial activity against wild strains (MIC range, 8-16μg/ml against E. coli, K. pneumoniae, A. baumannii, and P. aeruginosa). 6c exhibited no cytotoxicity against two mammalian cell lines. Therefore, compound 6c represents a promising lead for further optimization to overcome Gram-negative resistance alone or in combination therapy.
Beschreibung:Available online 5 November 2019
Gesehen am 02.04.2020
Beschreibung:Online Resource
ISSN:1768-3254
DOI:10.1016/j.ejmech.2019.111850

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