Impact of Pyridyl Moieties on the Inhibitory Properties of Prominent Acyclic Metal Chelators Against Metallo-β-Lactamase-Producing Enterobacteriaceae: Investigating the Molecular Basis of Acyclic Metal Chelators' Activity

Sphelele C. Sosibo, Anou M. Somboro, Daniel G. Amoako, John Osei Sekyere, Linda A. Bester, Jane C. Ngila, Darren D. Sun, Hezekiel M. Kumalo

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Carbapenem-resistant Enterobacteriaceae (CREs)-mediated infections remain a huge public health concern. CREs produce enzymes such as metallo-β-lactamases (MBLs), which inactivate β-lactam antibiotics. Hence, developing efficient molecules capable of inhibiting these enzymes remains a way forward to overcoming this phenomenon. In this study, we demonstrate that pyridyl moieties favor the inhibitory activity of cyclic metal-chelating agents through in vitro screening, molecular modeling, and docking assays. Di-(2-picolyl) amine and tris-(2-picolyl) amine exhibited great efficacy against different types of MBLs and strong binding affinity for NDM-1, whereas 2-picolyl amine did not show activity at a concentration of 64 mg/L in combination with meropenem; it further showed the lowest binding affinity from computational molecular analysis, commensurating with the in vitro screening assays. The findings revealed that the pyridyl group plays a vital role in the inhibitory activity of the tested molecules against CREs and should be exploited as potential MBL inhibitors.

Original languageEnglish
Pages (from-to)439-449
Number of pages11
JournalMicrobial Drug Resistance
Volume25
Issue number3
DOIs
Publication statusPublished - Apr 2019

Keywords

  • Enterobacteriaceae
  • binding affinity
  • metal chelator
  • metallo-b-lactamase inhibitors
  • pyridyls

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Pharmacology
  • Microbiology (medical)

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