The significance of GlgE as a new target for tuberculosis.

Abstract

Largely neglected by the industrialized world for decades, tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis, has made a fulminant return to the public health agenda as a major global health threat. The worsening of the TB pandemic is driven by the rapid emergence of multidrug-resistant and extensively drug-resistant M. tuberculosis strains, which are virtually untreatable with current chemotherapies. The search for new strategies to combat such resistant strains is of paramount importance for control of the TB pandemic. In searching for new vulnerable processes in M. tuberculosis to enable the rational design of more efficient anti-TB chemotherapy, a novel class of antimycobacterial drug targets has recently been discovered; it is represented by GlgE, an essential maltosyltransferase that elongates linear α-glucans as part of a synthetic lethal biosynthetic pathway. Inactivation of GlgE causes accumulation of a toxic phosphosugar intermediate, maltose 1-phosphate, which drives the bacilli into a suicidal self-poisoning cycle that elicits a complex stress profile, eventually resulting in DNA damage and death of M. tuberculosis. GlgE combines many favorable properties that make it a highly attractive novel drug target for chemotherapy of TB.