Abstract
Mycobacterium tuberculosis (Mtb) must cope with exogenous oxidative stress imposed by the host. Unlike other antioxidant enzymes, Mtb’s thioredoxin reductase TrxB2 has been predicted to be essential not only to fight host defenses but also for in vitro growth. However, the specific physiological role of TrxB2 and its importance for Mtb pathogenesis remain undefined. Here we show that genetic inactivation of thioredoxin reductase perturbed several growth-essential processes, including sulfur and DNA metabolism and rapidly killed and lysed Mtb. Death was due to cidal thiol-specific oxidizing stress and prevented by a disulfide reductant. In contrast, thioredoxin reductase deficiency did not significantly increase susceptibility to oxidative and nitrosative stress. In vivo targeting TrxB2 eradicated Mtb during both acute and chronic phases of mouse infection. Deliberately leaky knockdown mutants identified the specificity of TrxB2 inhibitors and showed that partial inactivation of TrxB2 increased Mtb’s susceptibility to rifampicin. These studies reveal TrxB2 as essential thiol-reducing enzyme in Mtb in vitro and during infection, establish the value of targeting TrxB2, and provide tools to accelerate the development of TrxB2 inhibitors.
Highlights
Endogenous oxidative stress represents an inevitable challenge for microbes adapted to an aerobic lifestyle [1]
We demonstrate that targeting thioredoxin reductase TrxB2 eradicates Mycobacterium tuberculosis (Mtb) during acute and chronic mouse infections
TrxB2 Is Critical for Disulfide/Dithiol Redox Control in M. tuberculosis
Summary
Endogenous oxidative stress represents an inevitable challenge for microbes adapted to an aerobic lifestyle [1]. Pathogens like Mycobacterium tuberculosis (Mtb) are confronted with exogenous oxidative stress imposed by the host [2]. The production of antimicrobial oxidants is a critical host defense mechanism against Mtb [3,4]. Patients with germline mutations in phagocyte NADPH oxidase resulting in an impaired macrophage respiratory burst are predisposed to mycobacterial diseases including tuberculosis [5]. Mice lacking inducible nitric oxide synthase succumb to Mtb infection much faster than their wild type littermates [3]. The reactive oxygen and nitrogen species generated by these host enzymes can inactivate microbial iron-dependent enzymes, damage lipids and destroy DNA [1,6]
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