Degradation of mirubactin to multiple siderophores with varying Fe(<scp>iii</scp>) chelation properties

Pu, Hong; Jiang, Ting; Peng, Dian; Xia, Juanjuan; Gao, Juan; Wang, Yeji; Yan, Xiaohui; Huang, Xueshuang; Duan, Yanwen; Huang, Yong

doi:10.1039/d2ob00942k

Cited by 4 publications

(7 citation statements)

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“…The structure of the compound turned out to be identical to a recently described compound, Mirubactin C ( Pu et al, 2022 ), which belongs to a family of related compounds including mirubactin A, chlorocatechelin A and chlorocatechelin B. Mirubactin C is identical to mirubactin A, except that it is missing one of its 2,3-dihydroxybenzoid acid moieties and has lost the guanidine group. The relationship between mirubactin A and mirubactin C is similar to that of chlorocatechelin A to B ( Kishimoto et al, 2014 ).…”

Section: Resultsmentioning

confidence: 68%

“…Mirubactin A has a high affinity for Fe 3+ due to its hexadentate coordination potential based on its DHBA (x2) and hydroxamate moieties. Mirubactin C has a lower affinity for Fe 3+ because of the absence of one of the DHBA groups (Pu et al, 2022). However, mirubactin C is clearly capable of binding Fe because: first, the inhibitory effect we saw in cultures treated with ≥ 16 µg/ml mirubactin C was exacerbated by various mutations affected in iron uptake Frontiers in Microbiology 07 frontiersin.org Cellular Fe and Mg content of Bacillus subtilis 168CA and mbl, mreB, mutant cells, as determined by ICP-MS, after culture in PAB medium with/without supplementation with 20 mM MgSO 4 or 10 µg/ml mirubactin C. P-values are given for selected conditions which were calculated using the pairwise t-test function of the ggpubr package in R.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Kishimoto et al (2014Kishimoto et al ( , 2015a proposed that chlorocatechelin A spontaneously decomposes to give chlorocatechelin B under acidic conditions, (Kishimoto et al, 2014(Kishimoto et al, , 2015a raising the possibility that mirubactin C has a similar relationship as a degradation product of mirubactin A (Supplementary Figure 4). This was recently shown by Pu et al (2022). To check whether mirubactin A was produced by MAD8-470, the strain was cultured in 50 ml of GYM media for 3 days and, after removing the bacterial cells, the chemical profile of culture media was directly analysed by LC-MS. Mirubactin A was detected in both apo (m/z 605.2) and holo (m/z 658.1) forms (Giessen et al, 2012).…”

Section: Mirubactin C Is a Fragment Of The Siderophore Antibiotic Mir...mentioning

confidence: 92%

“…Actinomycetes have been a rich source of bioactive natural products including many diverse drugs, particularly antibiotics ( Genilloud, 2017 ). By screening a collection of actinomycete extracts we were able to identify, isolate and characterize a small natural product molecule, mirubactin C ( Pu et al, 2022 ), which efficiently rescues the growth of an mbl mutant in the absence of added Mg 2+ . We used bioactivity-guided fractionation to purify the molecule and determined its structure by a combination of NMR and high resolution mass spectrometry.…”

Section: Introductionmentioning

confidence: 99%

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Mirubactin C rescues the lethal effect of cell wall biosynthesis mutations in Bacillus subtilis

et al. 2022

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Growth of most rod-shaped bacteria is accompanied by the insertion of new peptidoglycan into the cylindrical cell wall. This insertion, which helps maintain and determine the shape of the cell, is guided by a protein machine called the rod complex or elongasome. Although most of the proteins in this complex are essential under normal growth conditions, cell viability can be rescued, for reasons that are not understood, by the presence of a high (mM) Mg2+ concentration. We screened for natural product compounds that could rescue the growth of mutants affected in rod-complex function. By screening > 2,000 extracts from a diverse collection of actinobacteria, we identified a compound, mirubactin C, related to the known iron siderophore mirubactin A, which rescued growth in the low micromolar range, and this activity was confirmed using synthetic mirubactin C. The compound also displayed toxicity at higher concentrations, and this effect appears related to iron homeostasis. However, several lines of evidence suggest that the mirubactin C rescuing activity is not due simply to iron sequestration. The results support an emerging view that the functions of bacterial siderophores extend well beyond simply iron binding and uptake.

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Section: Resultsmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Mirubactin C Is a Fragment Of The Siderophore Antibiotic Mir...mentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Mirubactin C rescues the lethal effect of cell wall biosynthesis mutations in Bacillus subtilis

et al. 2022

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On the mechanisms of lysis triggered by perturbations of bacterial cell wall biosynthesis

Kawai

Mackenzie

et al. 2023

Nat Commun

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Inhibition of bacterial cell wall synthesis by antibiotics such as β-lactams is thought to cause explosive lysis through loss of cell wall integrity. However, recent studies on a wide range of bacteria have suggested that these antibiotics also perturb central carbon metabolism, contributing to death via oxidative damage. Here, we genetically dissect this connection in Bacillus subtilis perturbed for cell wall synthesis, and identify key enzymatic steps in upstream and downstream pathways that stimulate the generation of reactive oxygen species through cellular respiration. Our results also reveal the critical role of iron homeostasis for the oxidative damage-mediated lethal effects. We show that protection of cells from oxygen radicals via a recently discovered siderophore-like compound uncouples changes in cell morphology normally associated with cell death, from lysis as usually judged by a phase pale microscopic appearance. Phase paling appears to be closely associated with lipid peroxidation.

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On the mechanisms of lysis triggered by perturbations of bacterial cell wall biosynthesis

Kawai

Mackenzie

et al. 2022

Preprint

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Cell wall synthesis is an essential function for the growth of almost all bacteria, and a major target for our most effective antibiotics. Inhibition of cell wall synthesis by antibiotics such as β-lactams is thought to cause explosive lysis through loss of cell wall integrity. However, recent studies on a wide range of bacteria have suggested that these antibiotics also perturb central carbon metabolism, contributing to death via oxidative damage. We have genetically dissected this connection in Bacillus subtilis and identified key enzymatic steps in upstream and downstream pathways that stimulate the generation of reactive oxygen species (ROS) through cellular respiration. Our results also reveal the critical role of iron homeostasis for the ROS-mediated lethal effects, through iron-dependent enhancement of lipid peroxidation when cell wall synthesis is perturbed. Unexpectedly, we found that protection of cells from ROS via a recently discovered siderophore-like compound uncoupled changes in cell morphology normally associated with cell death, from lysis as usually judged by a phase pale microscopic appearance. Phase paling appears to be specifically associated with lipid peroxidation, presumably the result of membrane destabilization. Finally, we provide a new view of the differentiated roles of the widely conserved Rod and aPBP mechanisms of bacterial cell wall synthesis.

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Degradation of mirubactin to multiple siderophores with varying Fe(iii) chelation properties

Abstract: Three siderophores mirubactins B―D (4―6) were identified as the degradation products of previously isolated mirubactin (1). Their structures were revealed by HR-ESI-MS/MS, NMR analyses, and density function calculations, in which...

Cited by 4 publications

References 28 publications

Mirubactin C rescues the lethal effect of cell wall biosynthesis mutations in Bacillus subtilis

Mirubactin C rescues the lethal effect of cell wall biosynthesis mutations in Bacillus subtilis

On the mechanisms of lysis triggered by perturbations of bacterial cell wall biosynthesis

On the mechanisms of lysis triggered by perturbations of bacterial cell wall biosynthesis

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