Organoarsenicals inhibit bacterial peptidoglycan biosynthesis by targeting the essential enzyme MurA

Area of Science:

• Microbiology
• Biochemistry
• Toxicology

Background:

• Trivalent organoarsenicals, such as methylarsenite (MAs(III)), are more toxic than inorganic arsenic species.
• MAs(III) exhibits significant antimicrobial activity, contributing to the arsenic biogeocycle, but its mechanism is poorly understood.

Purpose of the Study:

• To identify the molecular targets of MAs(III) in microbial systems.
• To explore the potential of organoarsenicals as novel antimicrobial agents.

Main Methods:

• A genomic library of Shewanella putrefaciens was screened in Escherichia coli for MAs(III) resistance.
• The identified S. putrefaciens murA gene (SpmurA) was overexpressed, and the purified SpMurA enzyme was tested for inhibition by various arsenic compounds and fosfomycin.
• Site-directed mutagenesis (C117D) was performed to investigate the mechanism of inhibition.

Main Results:

• Overexpression of SpmurA conferred MAs(III) resistance to E. coli.
• Purified SpMurA was inhibited by MAs(III) and phenylarsenite (PhAs(III)), but not by inorganic arsenite (As(III)).
• MAs(III) and fosfomycin demonstrated different inhibition mechanisms, as shown by the C117D mutant's resistance to fosfomycin but not MAs(III).

Conclusions:

• MurA, a key enzyme in peptidoglycan biosynthesis, is a target for MAs(III).
• Organoarsenicals represent a novel class of compounds with potential for developing new antimicrobial drugs.
• Understanding the mechanism of MAs(III) inhibition could aid in combating antibiotic resistance.