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.
Eman M E Dokla  1 ,  Nader S Abutaleb  2 ,  Sandra N Milik  3 ,  Daoyi Li  2 ,  Karim El-Baz  4 ,  Menna-Allah W Shalaby  5 ,  Rawan Al-Karaki  6 ,  Maha Nasr  7 ,  Christian D Klein  8 ,  Khaled A M Abouzid  9 ,  Mohamed N Seleem  10
Affiliations
  • 1. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt. Electronic address: [email protected].
  • 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: [email protected].
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.
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