Anion Inhibition Profiles of the γ-carbonic Anhydrase From the Pathogenic Bacterium Burkholderia Pseudomallei Responsible of Melioidosis and Highly Drug Resistant to Common Antibiotics

Bioorg Med Chem. 2017 Jan 15;25(2):575-580. doi: 10.1016/j.bmc.2016.11.021. Epub 2016 Nov 14.

Abstract

Burkholderia pseudomallei is a Gram-negative saprophytic bacterium responsible of melioidosis, an endemic disease of tropical and sub-tropical regions of the world. A recombinant γ-CA (BpsγCA) identified in the genome of this bacterium was cloned and purified. Its catalytic activity and anion inhibition profiles were investigated. The enzyme was an efficient catalyst for the CO2 hydration showing a kcat of 5.3×105s-1 and kcat/Km of 2.5×107M-1×s-1. The best BpsγCA inhibitors were sulfamide, sulfamic acid, phenylboronic acid and phenylarsonic acid, which showed KI in the range of 49-83μM (these inhibitors showed millimolar inhibition constant against hCA II), followed by diethyldithiocarbamate, selenate, tellurate, perrhenate, selenocyanate, trithiocarbonate, tetraborato, pyrophosphate, stannate, carbonate, bicarbonate, azide, cyanide, thiocyanate and cyanate with KIs in the range of 0.55-9.1mM. In our laboratories, work is in progress to resolve the X-ray crystal structures of BpsγCA, which may allow the development of small molecule inhibitors with desired properties for targeting and inhibiting specifically the bacterial over the human CAs, considering the fact that B. pseudomallei is involved in a serious bacterial disease.

Keywords: Anion; Burkholderia pseudomallei; Carbonic anhydrase; Inhibitor; Metalloenzymes; γ-Class.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anions / chemical synthesis
  • Anions / chemistry
  • Anions / pharmacology
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Burkholderia pseudomallei / drug effects*
  • Burkholderia pseudomallei / enzymology
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / metabolism*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Resistance, Bacterial / drug effects*
  • Humans
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Anions
  • Anti-Bacterial Agents
  • Carbonic Anhydrase Inhibitors
  • Carbonic Anhydrases