Development of benzimidazole-based derivatives as antimicrobial agents and their synergistic effect with colistin against gram-negative bacteria
Abutaleb, Nader S; Milik, Sandra N; Li, Daoyi; El-Baz, Karim; Shalaby, Menna-Allah W; Al-Karaki, Rawan; Nasr, Maha; Klein, Christian D; Seleem, Mohamed N; Dokla, Eman; Khaled A M Abouzid;
Abstract
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 2 μg/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, 8-16 μg/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.
Other data
Title | Development of benzimidazole-based derivatives as antimicrobial agents and their synergistic effect with colistin against gram-negative bacteria | Authors | Abutaleb, Nader S; Milik, Sandra N; Li, Daoyi; El-Baz, Karim; Shalaby, Menna-Allah W; Al-Karaki, Rawan; Nasr, Maha ; Klein, Christian D; Seleem, Mohamed N; Dokla, Eman ; Khaled A M Abouzid | Keywords | Antibiotic synergy;Antimicrobial resistance;Benzimidazole;Gram-negative bacteria;Phenotypic screening | Issue Date | 15-Jan-2020 | Publisher | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER | Journal | European Journal of Medicinal Chemistry | Volume | 186 | ISSN | 0223-5234 | DOI | 10.1016/j.ejmech.2019.111850 | PubMed ID | 31735572 | Scopus ID | 2-s2.0-85075481915 | Web of science ID | WOS:000509616800012 |
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