A non-beta-lactam antibiotic inhibitor for enterohemorrhagic Escherichia coli O104:H4

• Published in: Journal of molecular medicine (Berlin, Germany) Vol. 97; no. 9; pp. 1285 - 1297
• Main Authors: Wang, Haoqi, Jayaraman, Arul, Menon, Rani, Gejji, Varun, Karthikeyan, R., Fernando, Sandun
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2019; Springer Nature B.V
• Subjects: Antibiotics; Bacteria; Biomedical and Life Sciences; Biomedicine; Coliforms; Drug delivery; Drug resistance; E coli; Escherichia coli; Gram-negative bacteria; Human Genetics; Internal Medicine; Lead compounds; Molecular Medicine; Multidrug resistance; Original Article; Penicillin; Penicillin-binding protein; Pharmacophores; Strains (organisms); β-Lactam antibiotics; Dynamic simulation; Non-β-lactam inhibitor; β-Lactamase; O104: H4; E. coli O104: H4
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-019-01803-y

The overuse of antibiotics has caused an increased prevalence of drug-resistant bacteria. Bacterial resistance in E. coli is regulated via production of β-lactam-hydrolyzing β-lactamases enzymes. Escherichia coli O104: H4 is a multi-drug resistant strain known to resist β-lactam as well as several other antibiotics. Here, we report a molecular dynamic simulation–combined docking approach to identify, screen, and verify active pharmacophores against enterohemorrhagic Escherichia coli (EHEC). Experimental studies revealed a boronic acid cyclic monomer (BACM), a non-β-lactam compound, to inhibit the growth of E. coli O104: H4. In vitro Kirby Bauer disk diffusion susceptibility testing coupled interaction analysis suggests BACM inhibits E. coli O104:H4 growth by not only inhibiting the β-lactamase pathway but also via direct inhibition of the penicillin-binding protein. These results suggest that BACM could be used as a lead compound to develop potent drugs targeting beta-lactam resistant Gram-negative bacterial strains. Key messages • An in silico approach was reported to identify pharmacophores against E. coli O104: H4. • In vitro studies revealed a non-β-lactam compound to inhibit the growth of E. coli O104: H4. • This non-β-lactam compound could be used as a lead compound for targeting beta-lactam strains.