Benzothiazinones Kill <i>Mycobacterium tuberculosis</i> by Blocking Arabinan Synthesis

TLDR

New drugs are needed to combat the tuberculosis pandemic. The study reports the synthesis and characterization of 1,3‑benzothiazin‑4‑ones (BTZs), a novel class of antimycobacterial agents that kill *Mycobacterium tuberculosis* in vitro, ex vivo, and in mouse models. BTZs inhibit decaprenylphosphoryl‑β‑d‑ribose 2′‑epimerase, blocking production of decaprenylphosphoryl arabinose—a key precursor for cell‑wall arabinans—and thereby causing cell lysis and bacterial death. BTZ043, the most advanced compound, is a promising candidate for combination therapy against both drug‑sensitive and extensively drug‑resistant TB.

Abstract

New drugs are required to counter the tuberculosis (TB) pandemic. Here, we describe the synthesis and characterization of 1,3-benzothiazin-4-ones (BTZs), a new class of antimycobacterial agents that kill Mycobacterium tuberculosis in vitro, ex vivo, and in mouse models of TB. Using genetics and biochemistry, we identified the enzyme decaprenylphosphoryl-beta-d-ribose 2'-epimerase as a major BTZ target. Inhibition of this enzymatic activity abolishes the formation of decaprenylphosphoryl arabinose, a key precursor that is required for the synthesis of the cell-wall arabinans, thus provoking cell lysis and bacterial death. The most advanced compound, BTZ043, is a candidate for inclusion in combination therapies for both drug-sensitive and extensively drug-resistant TB.