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

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

doi:10.1016/j.ejmech.2019.111850

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

Eur J Med Chem. 2020 Jan 15:186:111850. doi: 10.1016/j.ejmech.2019.111850. Epub 2019 Nov 5.

Authors

Affiliations

¹ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt. Electronic address: emanelawady@pharma.asu.edu.eg.
² Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, 47907, USA.
³ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt; Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology (IPMB), Heidelberg University, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany.
⁴ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt; Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul, 136-791, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology (UST), Gajungro 217, Youseong-gu, Daejeon 305-350, Republic of Korea.
⁵ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt.
⁶ Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Mutah University, Karak, 61710, Jordan.
⁷ Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt.
⁸ Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology (IPMB), Heidelberg University, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany.
⁹ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt; Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Egypt.
¹⁰ Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, 47907, USA; Purdue Institute of Inflammation, Immunology, and Infectious Disease, West Lafayette, IN, 47907, USA. Electronic address: mseleem@purdue.edu.

PMID: 31735572
DOI: 10.1016/j.ejmech.2019.111850

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.

Keywords: Antibiotic synergy; Antimicrobial resistance; Benzimidazole; Gram-negative bacteria; Phenotypic screening.

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Benzimidazoles / chemical synthesis
Benzimidazoles / chemistry
Benzimidazoles / pharmacology*
Colistin / chemistry
Colistin / pharmacology*
Dose-Response Relationship, Drug
Gram-Negative Bacteria / drug effects*
Humans
Microbial Sensitivity Tests
Molecular Structure
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Benzimidazoles
Colistin