Inhibition of bacterial thioredoxin reductase: an antibiotic mechanism targeting bacteria lacking glutathione

Lu, Jun; Vlamis-Gardikas, Alexios; Kandasamy, K.; Zhao, Rong; Gustafsson, T.; Engstrand, Lars; Hoffner, Sven; Engman, Lars; Holmgren, Arne

doi:10.1096/fj.12-223305

Cited by 153 publications

(182 citation statements)

References 46 publications

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“…Downregulation or inhibition of Trx sensitized, whereas downregulation of TXNIP blunted the cell response to ADR. Of note, the important role of TrxR in prevention of oxidative cell injury has been previously documented (Andoh et al, 2002;Fang and Holmgren, 2006;Du et al, 2009;Carvalho et al, 2011;Lopert et al, 2012;Lu et al, 2013). Our results thus indicate that increasing Trx reducing activities is the major mechanism behind the antioxidative effect of AMPK.…”

Section: Ampk Attenuates Oxidative Cell Injurysupporting

confidence: 75%

5′-AMP-Activated Protein Kinase Attenuates Adriamycin-Induced Oxidative Podocyte Injury through Thioredoxin-Mediated Suppression of the Apoptosis Signal-Regulating Kinase 1–P38 Signaling Pathway

et al. 2013

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Oxidative stress-induced podocyte injury is one of the major mechanisms underlying the initiation and progression of glomerulosclerosis. 59-AMP-activated protein kinase (AMPK), a serine/threonine kinase that senses intracellular energy status and maintains energy homeostasis, is reported to have antioxidative effects. However, little is known about its application and mechanism. In this study, we investigated whether and how AMPK affected oxidative podocyte injury induced by Adriamycin (ADR; Wako Pure Chemical, Osaka, Japan). Exposure of podocytes to ADR resulted in cell injury, which was preceded by increased reactive oxygen species (ROS) generation and P38 activation. Prevention of oxidative stress with the antioxidant Nacetyl-cysteine and glutathione or inhibition of P38 with SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole] attenuated cell injury. Activation of AMPK with three structurally different AMPK activators also protected podocytes from ADR-elicited cell injury. This effect was associated with strong suppression of oxidative stress-sensitive kinase apoptosis signal-regulating kinase 1 (ASK1) and P38 without obvious influence on ROS level. Further analyses revealed that AMPK promoted thioredoxin (Trx) binding to ASK1. Consistently, AMPK potently suppressed the expression of thioredoxin-interacting protein (TXNIP), a negative regulator of Trx, whereas it significantly enhanced the activity of Trx reductases that convert oxidized Trx to reduced form. In further support of a key role of Trx, downregulation or inhibition of Trx exaggerated but downregulation of TXNIP attenuated the cell injury. These results indicate that AMPK prevents oxidative cell injury through Trx-mediated suppression of ASK1-P38 signaling pathway. Our findings thus provide novel mechanistic insights into the antioxidative actions of AMPK. AMPK could be developed as a novel therapeutic target for treatment of oxidative cell injury.

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Section: Ampk Attenuates Oxidative Cell Injurysupporting

confidence: 75%

5′-AMP-Activated Protein Kinase Attenuates Adriamycin-Induced Oxidative Podocyte Injury through Thioredoxin-Mediated Suppression of the Apoptosis Signal-Regulating Kinase 1–P38 Signaling Pathway

et al. 2013

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“…Involvement of reactive-oxygen species in the bactericidal effect of antibiotics was proposed (25)(26)(27). On the other hand, it was reported that thioredoxin plays a protective role against oxidative stress in bacteria (28)(29)(30)(31)(32). In S. aureus COL, there are three putative thioredoxins, SACOL1794 (Trx), SACOL0875, and SACOL1155.…”

Section: Resultsmentioning

confidence: 99%

Mutations in mmpL and in the Cell Wall Stress Stimulon Contribute to Resistance to Oxadiazole Antibiotics in Methicillin-Resistant Staphylococcus aureus

Xiao

Vakulenko

Chang

et al. 2014

Antimicrob Agents Chemother

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Staphylococcus aureus is a leading cause of hospital-and community-acquired infections, which exhibit broad resistance to various antibiotics. We recently disclosed the discovery of the oxadiazole class of antibiotics, which has in vitro and in vivo activities against methicillin-resistant S. aureus (MRSA). We report herein that MmpL, a putative member of the resistance, nodulation, and cell division (RND) family of proteins, contributes to oxadiazole resistance in the S. aureus strain COL. Through serial passages, we generated two S. aureus COL variants that showed diminished susceptibilities to an oxadiazole antibiotic. The MICs for the oxadiazole against one strain (designated S. aureus COL I ) increased reproducibly 2-fold (to 4 g/ml), while against the other strain (S. aureus COL R ), they increased >4-fold (to >8 g/ml, the limit of solubility). The COL R strain was derived from the COL I strain. Whole-genome sequencing revealed 31 mutations in S. aureus COL R , of which 29 were shared with COL I . Consistent with our previous finding that oxadiazole antibiotics inhibit cell wall biosynthesis, we found 13 mutations that occurred either in structural genes or in promoters of the genes of the cell wall stress stimulon. Two unique mutations in S. aureus COL R were substitutions in two genes that encode the putative thioredoxin (SACOL1794) and MmpL (SACOL2566). A role for mmpL in resistance to oxadiazoles was discerned from gene deletion and complementation experiments. To our knowledge, this is the first report that a cell wall-acting antibiotic selects for mutations in the cell wall stress stimulon and the first to implicate MmpL in resistance to antibiotics in S. aureus.

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“…Furthermore, class C compounds were chemically interesting, as all seven members of this class had a substructure of 2-phenyl-2,3-dihydro-1,2-benzothiazol-3-one; this compound substructure is also called ebsulfur. 25,26 Using compound 1 as a positive control hDAAO inhibitor, we characterized, in a panel of biochemical assays, properties of commercially available compounds with the class C substructure. Although these compounds were not the exact compounds emerging from the HTS, because of their chemical similarity, they are furthered referred to as "class C compounds."…”

Section: Biochemical Characterization Of Class C Compound Hdaao Inhibmentioning

confidence: 99%

High-Throughput Screening Strategy Identifies Allosteric, Covalent Human D-Amino Acid Oxidase Inhibitor

et al. 2015

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Genome-wide association studies have linked polymorphisms in the gene G72 to schizophrenia risk in several human populations. Although controversial, biochemical experiments have suggested that the mechanistic link of G72 to schizophrenia is due to the G72 protein product, pLG72, exerting a regulatory effect on human D-amino acid oxidase (hDAAO) activity. In an effort to identify hDAAO inhibitors of novel mechanism of action, we designed a pLG72-directed hDAAO activity assay suitable for high-throughput screening (HTS). During assay development, we confirmed that pLG72 was an inhibitor of hDAAO. Thus, our assay employed an IC 20 pLG72 concentration that was high enough to allow dynamic pLG72-hDAAO complexes to form but with sufficient remaining hDAAO activity to measure during an HTS. After conducting an approximately 150,000-compound HTS, we further characterized a class of compound hits that were less potent hDAAO inhibitors when pLG72 was present. Focusing primarily on compound, we demonstrated that these compounds inhibited hDAAO via an allosteric, covalent mechanism. Although there is significant interest in the therapeutic potential of compound 2 and its analogues, their sensitivity to reducing agents and their capacity to bind cysteines covalently would need to be addressed during therapeutic drug development.

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Inhibition of bacterial thioredoxin reductase: an antibiotic mechanism targeting bacteria lacking glutathione

Cited by 153 publications

References 46 publications

5′-AMP-Activated Protein Kinase Attenuates Adriamycin-Induced Oxidative Podocyte Injury through Thioredoxin-Mediated Suppression of the Apoptosis Signal-Regulating Kinase 1–P38 Signaling Pathway

5′-AMP-Activated Protein Kinase Attenuates Adriamycin-Induced Oxidative Podocyte Injury through Thioredoxin-Mediated Suppression of the Apoptosis Signal-Regulating Kinase 1–P38 Signaling Pathway

Mutations in mmpL and in the Cell Wall Stress Stimulon Contribute to Resistance to Oxadiazole Antibiotics in Methicillin-Resistant Staphylococcus aureus

High-Throughput Screening Strategy Identifies Allosteric, Covalent Human D-Amino Acid Oxidase Inhibitor

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