Inhibition of Bacillus anthracis metallo-β-lactamase by compounds with hydroxamic acid functionality

Abstract

Metallo-β-lactamases (MBLs) that catalyze hydrolysis of β-lactam antibiotics are an emerging threat due to their rapid spread. A strain of the bacterium Bacillus anthracis has its ability to produce and secrete a MBL, referred to Bla2. To address this challenge, novel hydroxamic acid-containing compounds such as 3-(heptyloxy)-N-hydroxybenzamide (compound 4) and N-hydroxy-3-((6-(hydroxyamino)-6-oxohexyl)oxy)benzamide (compound 7) were synthesized. Kinetic analysis of microbial inhibition indicated that the both sides of hydroxamic acids containing compound 7 revealed a reversible, competitive inhibition with a K_i value of 0.18 ± 0.06 μM. The result has reflected that the both sides of dihydroxamic acids in a molecule play a crucial role in the binding affinity rather than monohydroxamic containing compound 4 which was unable to inhibit Bla2. In addition, in silico analysis suggested that compound 7 was coordinated with a zinc ion in the active site of enzyme. These observations suggest that the dihydroxamic acid-containing compound may be a promising drug candidate, and a further implication for designing new inhibitors of Bla2.

Keywords:

• Enzyme kinetics
• inhibition
• lactamase

Acknowledgements

Authors also thank Prof. Charles Garner for data acquisition of ¹H, ¹³C NMR on 500 MHz supported by the NSF (Award #CHE-042802) and Dr. Alejandro Ramirez for data analysis of High-Resolution Mass Spectroscopy using + ESI at Baylor University. H.S. participated in writing this manuscript as a corresponding author.

Declaration of interest

The authors report no declaration of interest. This work was funded by FRC at Northeastern State University (to S-K.K.), and Welch Departmental Grant (Z-0036) and Sam Taylor Fellowship at McMurry University (to H.S.).

Supplementary material available online

Supplementary Figures S1–S3.