Inhibition of aryl acid adenylation domains involved in bacterial siderophore synthesis

Miethke, Marcus; Bisseret, Philippe; Beckering, Carsten L.; Vignard, David; Eustache, Jacques; Marahiel, Mohamed A.

doi:10.1111/j.1742-4658.2005.05077.x

Cited by 83 publications

(111 citation statements)

References 29 publications

(37 reference statements)

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“…The in vitro and in-culture inhibition efficacy of SAL-AMS was confirmed in further studies (215,303,304,324). Due to the in vitro IC 50 values, which were in the range of the enzyme concentrations used, and the observed noncompetitive inhibition of the analogue with respect to salicylate, SAL-AMS was suggested to be a tight binding inhibitor (91 zyme inhibition were made during further studies with the same compound and several derivatives thereof; however, the compounds were always found to be fully competitive for both ATP and the corresponding aryl acid (44,215,304). Further sulfamate-linked analogues have been derivatized mainly in their aryl and glycosyl domains (Fig.…”

Section: Siderophore Pathway Inhibitorsmentioning

confidence: 68%

Siderophore-Based Iron Acquisition and Pathogen Control

Miethke

Marahiel

2007

Microbiol Mol Biol Rev

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1,413

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SUMMARY High-affinity iron acquisition is mediated by siderophore-dependent pathways in the majority of pathogenic and nonpathogenic bacteria and fungi. Considerable progress has been made in characterizing and understanding mechanisms of siderophore synthesis, secretion, iron scavenging, and siderophore-delivered iron uptake and its release. The regulation of siderophore pathways reveals multilayer networks at the transcriptional and posttranscriptional levels. Due to the key role of many siderophores during virulence, coevolution led to sophisticated strategies of siderophore neutralization by mammals and (re)utilization by bacterial pathogens. Surprisingly, hosts also developed essential siderophore-based iron delivery and cell conversion pathways, which are of interest for diagnostic and therapeutic studies. In the last decades, natural and synthetic compounds have gained attention as potential therapeutics for iron-dependent treatment of infections and further diseases. Promising results for pathogen inhibition were obtained with various siderophore-antibiotic conjugates acting as “Trojan horse” toxins and siderophore pathway inhibitors. In this article, general aspects of siderophore-mediated iron acquisition, recent findings regarding iron-related pathogen-host interactions, and current strategies for iron-dependent pathogen control will be reviewed. Further concepts including the inhibition of novel siderophore pathway targets are discussed.

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Section: Siderophore Pathway Inhibitorsmentioning

confidence: 68%

Siderophore-Based Iron Acquisition and Pathogen Control

Miethke

Marahiel

2007

Microbiol Mol Biol Rev

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1,413

1,302

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“…Siderophore synthesis has recently been identified as a target for antibiotic development (12,37,38). In these studies, the NRPS adenylation domain has served as the target for inhibitor design.…”

Section: Discussionmentioning

confidence: 99%

The 1.8 Å Crystal Structure of PA2412, an MbtH-like Protein from the Pyoverdine Cluster of Pseudomonas aeruginosa

Drake

Cao

et al. 2007

Journal of Biological Chemistry

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Many bacteria use nonribosomal peptide synthetase (NRPS) proteins to produce peptide antibiotics and siderophores. The catalytic domains of the NRPS proteins are usually linked in large multidomain proteins. Often, additional proteins are coexpressed with NRPS proteins that modify the NRPS peptide products, ensure the availability of substrate building blocks, or play a role in the import or export of the NRPS product. Many NRPS clusters include a small protein of ϳ80 amino acids with homology to the MbtH protein of mycobactin synthesis in Mycobacteria tuberculosis; no function has been assigned to these proteins. Pseudomonas aeruginosa utilizes an NRPS cluster to synthesize the siderophore pyoverdine. The pyoverdine peptide contains a dihydroxyquinoline-based chromophore, as well as two formyl-N-hydroxyornithine residues, which are involved in iron binding. The pyoverdine cluster contains four modular NRPS enzymes and 10 -15 additional proteins that are essential for pyoverdine production. Coexpressed with the pyoverdine synthetic enzymes is a 72-amino acid MbtH-like family member designated PA2412. We have determined the three-dimensional structure of the PA2412 protein and describe here the structure and the location of conserved regions. Additionally, we have further analyzed a deletion mutant of the PA2412 protein for growth and pyoverdine production. Our results demonstrate that PA2412 is necessary for the production or secretion of pyoverdine at normal levels. The PA2412 deletion strain is able to use exogenously produced pyoverdine, showing that there is no defect in the uptake or utilization of the iron-pyoverdine complex.Iron is an essential cofactor for many proteins, playing both catalytic and structural roles (1-3). Because of the low solubility of free Fe 3ϩ , many bacteria produce siderophores that bind to iron. The iron-siderophore complex is then actively transported into the cell. Although some small molecules like citrate or salicylate are able to function as lower affinity siderophores, many specialized peptides with extremely high affinity for iron are produced nonribosomally by bacteria. These compounds are produced by nonribosomal peptide synthetases (NRPSs) 2 that exist as modular proteins with multiple catalytic domains joined in a single protein. Often expressed with NRPS genes are other genes that encode proteins involved in additional essential steps including the synthesis of building blocks, siderophore export, import of the Fe 3ϩ -siderophore complex, or the removal Fe 3ϩ from the imported siderophore (4, 5). Pseudomonas aeruginosa is a bacterial pathogen that commonly causes infections in patients with cystic fibrosis (6). The siderophore pyoverdine (Fig. 1) is synthesized by P. aeruginosa (3) and has been correlated with virulence (7). Pyoverdine contains a cyclic peptide chain as well as a chemically modified dihydroxyquinoline-based chromophore that is responsible for iron binding. The peptide backbone of pyoverdine is synthesized by four large, multi-module NRPS proteins. The ...

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“…[42][43][44][63][64][65] In this report we have systematically investigated the SAR of the glycosyl domain of our salicyl-nucleoside bisubstrate inhibitor. In particular, in vitro results against MbtA showed that deletion of the 2′, 3′, and 4′ oxygen atoms were generally well tolerated, while modifications making the sugar more (13) or less (11) flexible were detrimental.…”

Section: Discussionmentioning

confidence: 99%

“…The homology model and docking runs were configured as described 43 , except that water molecules were held fixed during the conformational search. 10,000 search steps were performed for each compound.…”

Section: Docking Studiesmentioning

confidence: 99%

Antitubercular Nucleosides That Inhibit Siderophore Biosynthesis: SAR of the Glycosyl Domain

et al. 2006

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Tuberculosis (TB) is the leading cause of infectious disease mortality in the world by a bacterial pathogen. We previously demonstrated that a bisubstrate inhibitor of the adenylation enzyme MbtA, which is responsible for the second step of mycobactin biosynthesis, exhibited potent antitubercular activity. Here we systematically investigate the structure activity relationships of the bisubstrate inhibitor glycosyl domain resulting in the identification of a carbocyclic analogue that possesses a K I app value of 2.3 nM and MIC 99 values of 1.56 μM against M. tuberculosis H37Rv. The SAR data suggest the intriguing possibility that the bisubstrate inhibitors utilize a transporter for entry across the mycobacterial cell-envelope. Additionally, we report improved conditions for the expression of MbtA and biochemical analysis demonstrating that MbtA follows a random sequential enzyme mechanism for the adenylation half-reaction.

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Inhibition of aryl acid adenylation domains involved in bacterial siderophore synthesis

Cited by 83 publications

References 29 publications

Siderophore-Based Iron Acquisition and Pathogen Control

Siderophore-Based Iron Acquisition and Pathogen Control

The 1.8 Å Crystal Structure of PA2412, an MbtH-like Protein from the Pyoverdine Cluster of Pseudomonas aeruginosa

Antitubercular Nucleosides That Inhibit Siderophore Biosynthesis: SAR of the Glycosyl Domain

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