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

Sung-Kun Kim,Sung Joon Kim,Mara Demuth,Sara R Schlesinger,Jonathan Urbanczyk,Robert W Shaw,Hyunshun Shin

doi:10.1080/14756366.2016.1222580

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 Ki 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.

Highlights

The bacterium Bacillus anthracis is responsible for causing anthrax infection, which is often fatal[1]
Kinetic analysis of microbial inhibition indicated that the both sides of hydroxamic acids containing compound 7 revealed a reversible, competitive inhibition with a Ki value of 0.18 ± 0.06 mM
The primary cause of antibiotic resistance is the emergence of b-lactamases that catalyze the hydrolysis of b-lactam antibiotics such as penicillins, cephalosporins, and carbapenems[1]

Summary

Introduction

The bacterium Bacillus anthracis is responsible for causing anthrax infection, which is often fatal[1]. Increasing prevalence of antibiotic resistant B. anthracis is extending our inability to effectively resolve these infections[1,2]. The b-lactamases are categorized into four classes, i.e., A through D3. The Sterne strain of B. anthracis is capable of producing a MBL which is a B1 b-lactamase, called Bla[2], containing two zinc ions referred to as Zn1 and Zn24,5. B-Lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam are commercially available and can be used with existing antibiotics to cure some antibioticresistant infections, but these are not effective against MBLs. some potential inhibitors have the ability to inhibit

Methods

Results

Conclusion