Redox homeostasis in mycobacteria: the key to tuberculosis control?

Abstract

Mycobacterium tuberculosis (Mtb) is a metabolically flexible pathogen that has the extraordinary ability to sense and adapt to the continuously changing host environment experienced during decades of persistent infection. Mtb is continually exposed to endogenous reactive oxygen species (ROS) as part of normal aerobic respiration, as well as exogenous ROS and reactive nitrogen species (RNS) generated by the host immune system in response to infection. The magnitude of tuberculosis (TB) disease is further amplified by exposure to xenobiotics from the environment such as cigarette smoke and air pollution, causing disruption of the intracellular prooxidant–antioxidant balance. Both oxidative and reductive stresses induce redox cascades that alter Mtb signal transduction, DNA and RNA synthesis, protein synthesis and antimycobacterial drug resistance. As reviewed in this article, Mtb has evolved specific mechanisms to protect itself against endogenously produced oxidants, as well as defend against host and environmental oxidants and reductants found specifically within the microenvironments of the lung. Maintaining an appropriate redox balance is critical to the clinical outcome because several antimycobacterial prodrugs are only effective upon bioreductive activation. Proper homeostasis of oxido-reductive systems is essential for Mtb survival, persistence and subsequent reactivation. The progress and remaining deficiencies in understanding Mtb redox homeostasis are also discussed.

CysK2 from Mycobacterium tuberculosis Is an O -Phospho- l -Serine-Dependent S -Sulfocysteine Synthase

“…For UV-visible (UV-vis) spectrophotometry, absorption spectra of CysK2 were recorded at 12 M enzyme concentration in 100 mM Na-HEPES, pH 7.0, using a Jasco-V65 spectrophotometer. Spectra of reaction intermediates were recorded at time points 3,6,9,14,20,30,40, and 55 min after the addition of the substrates OPS and OAS to a 2 mM final concentration. The reverse reaction starting from L-cysteine or S-sulfocysteine was carried out under similar conditions.…”

“…The intracellular bacteria are exposed to reactive oxygen and reactive nitrogen species (ROS and RNS) generated by macrophages (2), and redox defense mechanisms are therefore crucial for the survival of this pathogen. In actinobacteria, mycothiol and other low-molecular-weight thiols, i.e., ergothioneine and small cysteine-containing redox proteins, serve as powerful and indispensable radical scavengers (3). Mutations leading to mycothiol depletion cause increased sensitivity to oxidative stress (2,4).…”

Biochemical Characterization of Isoniazid-resistant Mycobacterium tuberculosis: Can the Analysis of Clonal Strains Reveal Novel Targetable Pathways?

“…The net increase of the fatty acid oxidation enzymes suggests that lipids are an important source of energy for the INHr strains, with the generation of substantial quantities of NADPH [55] -oxidation activity in Mtb is also related to an altered energetic metabolism, with a possible higher production of ATP molecules. For instance,…”

“…-oxidation of palmitate generates 106 ATP molecules, while the oxidation of glucose yields only 38 ATP molecules [55]. The increased fatty acid oxidation pathway is concomitant with the increase of some proteins in the ATP synthase machinery and the adenylate cyclase enzyme (Rv1647) in both INHr strains (Table 1, Figure 3A), which also suggests a higher ATP production and hydrolysis -oxidation is also associated with the reduced levels of the pyruvate kinase (PykA) in the INHr strains (although only statistically significant for the clinical INHr, Figure 3A) that is related with the use of nonglycolytic carbon sources such as lipids [56].…”

Regulation of Ergothioneine Biosynthesis and Its Effect on Mycobacterium tuberculosis Growth and Infectivity

“…Xenobiotics, including free radicals, produced by the host to cope with infection; antibiotics; and general bacterial respiration are countered by an intricate detoxification system utilized by the bacterium that is composed of (a) enzymes such as catalase, superoxide dismutase, and alkyl hydroperoxidase; (b) truncated hemoglobins; (c) oxidoreductases; and (d) redox coupling systems (1). The most common defense mechanism against reactive oxygen and nitrogen species damage in eukaryotes and Gram-negative bacteria relies on glutathione, a low molecular weight thiol.…”