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

Somu, Ravindranadh V.; Wilson, Daniel J.; Bennett, Eric M.; Boshoff, Helena I.; Celia, Laura; Beck, Brian J.; Barry, Clifton E.; Aldrich, Courtney C.

doi:10.1021/jm061068d

Cited by 78 publications

(171 citation statements)

References 82 publications

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“…Related aminoacyl sulfamoyl adenosines were shown in previous studies to act as potent inhibitors of NRPS and non-NRPS A domains (94,210). 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).…”

Section: Siderophore Pathway Inhibitorsmentioning

confidence: 61%

“…Consequently, SAL-AMS was found to inhibit YbtE with a higher preference (1.8-fold) than DHB-AMS, and DHB-AMS inhibited DhbE preferentially better (1.25-fold) than SAL-AMS (215). A systematic investigation of structure-activity relationships of the glycosyl domain in sulfamate-bridged bisubstrate analogues resulted in the identification of a carbocyclic compound that inhibited MbtA in vitro and M. tuberculosis in iron-deficient cultures with an efficacy comparable to that observed for SAL-AMS (304). It was furthermore suggested that the bisubstrate inhibitors utilize a mycobacterial transporter for crossing the cell envelope.…”

Section: Siderophore Pathway Inhibitorsmentioning

confidence: 93%

“…It was furthermore suggested that the bisubstrate inhibitors utilize a mycobacterial transporter for crossing the cell envelope. The compounds that displayed a remarkable activity against M. tuberculosis had only slight activities against Y. pseudotuberculosis, which was suggested to be the result of different transport mechanisms (304). Further studies aimed to improve the overall stability and the anticipated ADMET (i.e., absorption, distribution, metabolism, elimination, and toxicology) profile (228a) of the SAL-AMS parent compound.…”

Section: Siderophore Pathway Inhibitorsmentioning

confidence: 99%

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Siderophore-Based Iron Acquisition and Pathogen Control

Miethke

Marahiel

2007

Microbiol Mol Biol Rev

1,440

1,302

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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: 61%

Section: Siderophore Pathway Inhibitorsmentioning

confidence: 93%

Section: Siderophore Pathway Inhibitorsmentioning

confidence: 99%

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Siderophore-Based Iron Acquisition and Pathogen Control

Miethke

Marahiel

2007

Microbiol Mol Biol Rev

1,440

1,302

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“…These differences may be due to the severity of the catabolic condition, since the latter study reported a 40% weight loss due to STZ treatment [83], compared to the ≤5% weight loss achieved in the present study. STZ is known to have toxic effects in mice, where the severity differs depending on the genetic background [84]. Finally, the toxic effects of STZ can extend to the pituitary, since acute STZ treatment leads to blockade of GH secretory vesicle release and somatotrope rupture [85].…”

Section: Discussionmentioning

confidence: 99%

Expression Analysis of Hypothalamic and Pituitary Components of the Growth Hormone Axis in Fasted and Streptozotocin-Treated Neuropeptide Y (NPY)-Intact (NPY<sup>+/+</sup>) and NPY-Knockout (NPY<sup> –/–</sup>) Mice

et al. 2005

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In the fasted and the streptozotocin (STZ)-induced diabetic male rat, hypothalamic growth hormone (GH)-releasing hormone (GHRH) mRNA levels, and pulsatile GH release are decreased. These changes are believed to be due to a rise in hypothalamic neuropeptide Y (NPY) that inhibits GHRH expression. To directly test if NPY is required for metabolic regulation of hypothalamic neuropeptides important in GH secretion, NPY, GHRH and somatostatin (SRIH) mRNA levels were determined in fasted (48 h) and STZ-treated wild-type (NPY^+/+) and NPY-knockout (NPY^–/–) mice by ribonuclease protection assay. In addition, pituitary receptor mRNA levels for GHRH (GHRH-R), ghrelin (GHS-R) and SRIH (sst2) were assessed by RT-PCR. Under fed conditions the GH axis of NPY^+/+ and NPY^–/– did not differ. In the NPY^+/+ mouse, fasting resulted in a 23% weight loss and >250% increase in NPY mRNA accompanied by a significant reduction in both GHRH and SRIH mRNA. These changes were associated with increases in pituitary expression of GHRH-R and GHS-R and a concomitant suppression of sst2. In the NPY^–/– mouse, fasting also resulted in a 23% weight loss and comparable changes in GHRH-R and sst2, but failed to alter GHRH, SRIH and GHS-R mRNA levels. Fasting resulted in an overall increase in circulating GH, which reached significance in the fasted NPY^–/– mouse. Induction of diabetes in NPY^+/+ mice, using a single, high-dose, STZ injection (150 mg/kg), resulted in modest weight loss (5%), and a 158% increase NPY expression which was associated with reciprocal changes in pituitary GHS-R and sst2 expression, similar to that observed in the fasted state, but no change in hypothalamic GHRH or SRIF expression was observed. Induction of diabetes in NPY^+/+ and NPY^–/– mice, using a multiple, low-dose, STZ paradigm (5 consecutive daily injections of 40 mg/kg), did not alter body weight, hypothalamic neuropeptide expression or pituitary receptor expression, with the exception that sst2 mRNA levels were suppressed and GH levels did rise in the NPY^–/– mouse. These observations demonstrate that NPY is not required for basal regulation of the GH axis, but is required for fasting-induced suppression of GHRH and SRIH expression, as well as fasting-induced augmentation of pituitary GHS-R mRNA. In contrast to the rat, fasting clearly did not suppress circulating GH levels in mice, but resulted in an overall rise in mean GH levels, similar to that observed in other mammalian species. The fact that many of the fasting-induced changes in the GH axis were observed in the high-dose STZ-treated mice, but were not observed in the multiple, low-dose paradigm, suggests STZ-mediated modulation of GH axis function is dependent on the severity of the catabolic state and not hyperglycemia.

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“…S1 in the supplemental material), that specifically targets MbtA by mimicking the salicyl-AMP intermediate (9)(10)(11). In vitro studies have confirmed that salicyl-AMS inhibits MbtA activity and also inhibits M. tuberculosis growth in iron-depleted media (9,12), with the MIC for M. tuberculosis H37Rv found to be 0.5 g/ml in a study with an alamarBlue assay (13). In this study, we have characterized the pharmacokinetics of salicyl-AMS and its therapeutic efficacy in a murine infection model, leading to the first in vivo proof of concept for the use of siderophore biosynthesis inhibitors as novel antibacterials.…”

mentioning

confidence: 96%