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Comparison of the structure and activity of thioredoxin 2 and thioredoxin 1 from Acinetobacter baumannii.

ABSTRACT: Thioredoxin (Trx) is essential in a redox-control system, with many bacteria containing two Trxs: Trx1 and Trx2. Due to a Trx system's critical function, Trxs are targets for novel antibiotics. Here, a 1.20 Å high-resolution structure of Trx2 from Acinetobacter baumannii (abTrx2), an antibiotic resistant pathogenic superbug, is elucidated. By comparing Trx1 and Trx2, it is revealed that the two Trxs possess similar activity, although Trx2 contains an additional N-terminal zinc-finger domain and exhibits more flexible properties in solution. Finally, it is shown that the Trx2 zinc-finger domain might be rotatable and that proper zinc coordination at the zinc-finger domain is critical to abTrx2 activity. This study enhances understanding of the Trx system and will facilitate the design of novel antibiotics.

SUBMITTER: Chang YJ

PROVIDER: S-EPMC9980383 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Comparison of the structure and activity of thioredoxin 2 and thioredoxin 1 from Acinetobacter baumannii.

Chang Ye Ji YJ Sung Ji Hye JH Lee Chang Sup CS Lee Jun Hyuck JH Park Hyun Ho HH

IUCrJ 20230301 Pt 2

Thioredoxin (Trx) is essential in a redox-control system, with many bacteria containing two Trxs: Trx1 and Trx2. Due to a Trx system's critical function, Trxs are targets for novel antibiotics. Here, a 1.20 Å high-resolution structure of Trx2 from Acinetobacter baumannii (abTrx2), an antibiotic resistant pathogenic superbug, is elucidated. By comparing Trx1 and Trx2, it is revealed that the two Trxs possess similar activity, although Trx2 contains an additional N-terminal zinc-finger domain and ...[more]

PMID: 36752373

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Project description:Acinetobacter baumannii, a Gram-negative coccobacillus, has become a prevalent nosocomial health threat affecting the majority of hospitals both in the U.S. and around the globe. Microbial cell surface hydrophobicity (CSH) has previously been correlated with virulence, uptake by immune cells, and attachment to epithelial cells. A mutant strain of A. baumannii (ΔtrxA) lacking the redox protein thioredoxin A was found to be more hydrophobic than its wild type (WT) and complemented counterparts, as measured by both Microbial Adhesion to Hydrocarbon (MATH) and salt aggregation. The hydrophobicity of the mutant could be abrogated through treatment with sodium cyanoborohydride (SCBH). This modulation correlated with reduction of disulfide bonds, as SCBH was able to reduce 5,5'-dithio-bis-[2-nitrobenzoic acid] and treatment with the known disulfide reducer, β-mercaptoethanol, also decreased ΔtrxA CSH. Additionally, the ΔtrxA mutant was more readily taken up than WT by J774 macrophages and this differential uptake could be abrogated though SCBH treatment. When partitioned into aqueous and hydrophobic phases, ΔtrxA recovered from the hydrophobic partition was phagocytosed more readily than from the aqueous phase further supporting the contribution of CSH to A. baumannii uptake by phagocytes. A second Gram-negative bacterium, Francisella novicida, also showed the association of TrxA deficiency (FnΔtrxA) with increased hydrophobicity and uptake by J774 cells. We previously have demonstrated that modification of the type IV pilus system (T4P) was associated with the A. baumannii ΔtrxA phenotype, and the Francisella FnΔtrxA mutant also was found to have a marked T4P deficiency. Interestingly, a F. novicida mutant lacking pilT also showed increased hydrophobicity over FnWT. Collective evidence presented in this study suggests that Gram-negative bacterial thioredoxin mediates CSH through multiple mechanisms including disulfide-bond reduction and T4P modulation.

Project description:Acinetobacter baumannii is an emergent bacterial pathogen that provokes many types of infections in hospitals around the world. The genome of this organism consists of a chromosome and plasmids. These plasmids vary over a wide size range and many of them have been linked to the acquisition of antibiotic-resistance genes. Our bioinformatic analyses indicate that A. baumannii plasmids belong to a small number of plasmid lineages. The general structure of these lineages seems to be very stable and consists not only of genes involved in plasmid maintenance functions but of gene sets encoding poorly characterized proteins, not obviously linked to survival in the hospital setting, and opening the possibility that they improve the parasitic properties of plasmids. An analysis of genes involved in replication, suggests that members of the same plasmid lineage are part of the same plasmid incompatibility group. The same analysis showed the necessity of classifying the Rep proteins in ten new groups, under the scheme proposed by Bertini et al. (2010). Also, we show that some plasmid lineages have the potential capacity to replicate in many bacterial genera including those embracing human pathogen species, while others seem to replicate only within the limits of the Acinetobacter genus. Moreover, some plasmid lineages are widely distributed along the A. baumannii phylogenetic tree. Despite this, a number of them lack genes involved in conjugation or mobilization functions. Interestingly, only 34.6% of the plasmids analyzed here possess antibiotic resistance genes and most of them belong to fourteen plasmid lineages of the twenty one described here. Gene flux between plasmid lineages appears primarily limited to transposable elements, which sometimes carry antibiotic resistance genes. In most plasmid lineages transposable elements and antibiotic resistance genes are secondary acquisitions. Finally, broad host-range plasmids appear to have played a crucial role.

Project description:Multidrug-resistant Acinetobacter baumannii is among the most common causes of infectious complications associated with combat-related trauma in military personnel serving overseas. However, little is currently known about its pathogenesis. While the gastrointestinal (GI) tract has been found to be a major reservoir for A. baumannii, as well as to potentially contribute to development of multidrug resistance, no studies have addressed the mechanisms involved in gut colonization. In this study, we address this critical gap in knowledge by first assessing the interaction between secretory IgA (SIgA), the principal humoral immune defense on mucosal surfaces, and the A. baumannii clinical isolate Ci79. Surprisingly, SIgA appeared to enhance A. baumannii GI tract colonization, in a process mediated by bacterial thioredoxin A (TrxA), as evidenced by reduction of bacterial attachment in the presence of TrxA inhibitors. Additionally, a trxA targeted deletion mutant (ΔtrxA) showed reduced bacterial burdens within the GI tract 24 h after oral challenge by in vivo live imaging, along with loss of thiol-reductase activity. Surprisingly, not only was GI tract colonization greatly reduced but the associated 50% lethal dose (LD50) of the ΔtrxA mutant was increased nearly 100-fold in an intraperitoneal sepsis model. These data suggest that TrxA not only mediates A. baumannii GI tract colonization but also may contribute to pathogenesis in A. baumannii sepsis following escape from the GI tract under conditions when the intestinal barrier is compromised, as occurs with cases of severe shock and trauma.IMPORTANCEAcinetobacter baumannii is an emerging bacterial pathogen recently classified as a serious threat to U.S. and global health by both the Centers for Disease Control and Prevention and the World Health Organization. It also is one of the leading causes of combat-related infections associated with injured military personnel serving overseas. Little is known regarding mechanisms of gastrointestinal tract colonization despite this site being shown to serve as a reservoir for multidrug-resistant (MDR) A. baumannii isolates. Here, we establish that secretory IgA, the major immunoglobulin of mucosal surfaces, promotes A. baumannii GI tract colonization via bacterial thioredoxin A as evidenced through significant reduction in colonization in IgA-deficient animals. Additionally, bacterial colonization and mortality were significantly reduced in animals challenged with a thioredoxin A-deficient A. baumannii mutant. Combined, these data suggest that thioredoxin A is a novel virulence factor, for which antithioredoxin therapies could be developed, for this important multidrug-resistant pathogen.

Dataset Information

Comparison of the structure and activity of thioredoxin 2 and thioredoxin 1 from Acinetobacter baumannii.

Publications

Comparison of the structure and activity of thioredoxin 2 and thioredoxin 1 from Acinetobacter baumannii.

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