Towards a new combination therapy for tuberculosis with next generation benzothiazinones

Abstract

The benzothiazinone lead compound, BTZ043, kills Mycobacterium tuberculosis by inhibiting the essential flavo-enzyme DprE1, decaprenylphosphoryl-beta-D-ribose 2-epimerase. Here, we synthesized a new series of piperazine-containing benzothiazinones (PBTZ) and show that, like BTZ043, the preclinical candidate PBTZ169 binds covalently to DprE1. The crystal structure of the DprE1-PBTZ169 complex reveals formation of a semimercaptal adduct with Cys387 in the active site and explains the irreversible inactivation of the enzyme. Compared to BTZ043, PBTZ169 has improved potency, safety and efficacy in zebrafish and mouse models of tuberculosis (TB). When combined with other TB drugs, PBTZ169 showed additive activity against M. tuberculosis in vitro except with bedaquiline (BDQ) where synergy was observed. A new regimen comprising PBTZ169, BDQ and pyrazinamide was found to be more efficacious than the standard three drug treatment in a murine model of chronic disease. PBTZ169 is thus an attractive drug candidate to treat TB in humans.Subject Categories Microbiology, Virology & Host Pathogen Interaction; Pharmacology & Drug Discovery

Design, Syntheses, and Anti-TB Activity of 1,3-Benzothiazinone Azide and Click Chemistry Products Inspired by BTZ043

“…BTZ043 6 and its closest congener, PBTZ169 7 (2), and analogues have been shown to kill Mtb in vitro, ex vivo, and in mouse models of TB.…”

The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis

“…More recently, the preclinical candidate PBTZ169 [2-[4-(cyclohexylmethyl) piperazin-1-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one] arose from a lead optimization campaign and is currently on track to enter clinical trials (3). PBTZ169 has an MIC against Mycobacterium tuberculosis of 0.3 ng/ml.…”

Animal Models of Tuberculosis: Zebrafish

“…Another example of using zebrafish embryos in the identification of new antimycobac- terial drugs is a recent study by Makarov, who produced and analyzed a new generation of benzathiozinones (Makarov et al 2014). These compounds bind DprE1 and thereby selectively inhibit the biosynthesis of crucial cell wall components.…”