The production of siderophore analogues using precursor-directed biosynthesis.

Siderophores are low-molecular-weight organic bacterial and fungal secondary metabolites that form high affinity complexes with Fe(III). These Fe(III)-siderophore complexes are part of the siderophore-mediated Fe(III) uptake mechanism, which is the most widespread strategy used by microbes to access sufficient iron for growth. Microbial competition for limited iron is met by biosynthetic gene clusters that encode for the biosynthesis of siderophores with variable molecular scaffolds and iron binding motifs.

Preterm infants harbour diverse populations, including atypical species that encode and produce an array of antimicrobial resistance- and virulence-associated factors.

spp. are frequently enriched in the gut microbiota of preterm neonates, and overgrowth is associated with necrotizing enterocolitis (NEC), nosocomial infections and late-onset sepsis. Little is known about the genomic and phenotypic characteristics of preterm-associated , as previous studies have focused on the recovery of antimicrobial-resistant isolates or culture-independent molecular analyses.

The chemical biology and coordination chemistry of putrebactin, avaroferrin, bisucaberin, and alcaligin.

Dihydroxamic acid macrocyclic siderophores comprise four members: putrebactin (putH), avaroferrin (avaH), bisucaberin (bisH), and alcaligin (alcH). This mini-review collates studies of the chemical biology and coordination chemistry of these macrocycles, with an emphasis on putH. These Fe(III)-binding macrocycles are produced by selected bacteria to acquire insoluble Fe(III) from the local environment.

Dimeric and trimeric homo- and heteroleptic hydroxamic acid macrocycles formed using mixed-ligand Fe(III)-based metal-templated synthesis.

Macrocyclic hydroxamic acids coordinate Fe(III) with high affinity as part of siderophore-mediated bacterial iron acquisition. Trimeric hydroxamic acid macrocycles, such as desferrioxamine E (DFOE), are prevalent in nature, with fewer dimeric macrocycles identified, including putrebactin (pbH), avaroferrin (avH), bisucaberin (bsH) and alcaligin (alH). This work used metal-templated synthesis (MTS) to pre-assemble complexes between one equivalent of Fe(III) and two equivalents of 4-((4-aminobutyl)(hydroxy)amino)-4-oxobutanoic acid (BBH) or 4-((5-aminopentyl)(hydroxy)amino)-4-oxobutanoic acid (PBH).

Mixing Up the Pieces of the Desferrioxamine B Jigsaw Defines the Biosynthetic Sequence Catalyzed by DesD.

Late-stage assembly of the trimeric linear siderophore desferrioxamine B (DFOB) native to Streptomyces pilosus involves two DesD-catalyzed condensation reactions between one N-acetyl-N-hydroxy-1,5-diaminopentane (AHDP) unit and two N-succinyl-N-hydroxy-1,5-diaminopentane (SHDP) units. AHDP and SHDP are products of DesBC-catalyzed reactions of the native diamine substrate 1,5-diaminopentane (DP). The sequence of DesD-catalyzed DFOB biosynthesis was delineated by analyzing the distribution of DFOB analogues and dimeric precursors assembled by S.

Simultaneous biosynthesis of putrebactin, avaroferrin and bisucaberin by Shewanella putrefaciens and characterisation of complexes with iron(III), molybdenum(VI) or chromium(V).

Cultures of Shewanella putrefaciens grown in medium containing 10mM 1,4-diamino-2-butanone (DBO) as an inhibitor of ornithine decarboxylase and 10mM 1,5-diaminopentane (cadaverine) showed the simultaneous biosynthesis of the macrocyclic dihydroxamic acids: putrebactin (pbH), avaroferrin (avH) and bisucaberin (bsH). The level of DBO did not completely repress the production of endogenous 1,4-diaminobutane (putrescine) as the native diamine substrate of pbH. The relative concentration of pbH:avH:bsH was 1:2:1, which correlated with the substrate selection of putrescine:cadaverine in a ratio of 1:1.

Dinuclear [(V(V)O(putrebactin))2(μ-OCH3)2] formed in solution as established from LC-MS measurements using 50V-enriched V2O5.

Analysis of 1:1 solutions of V(V) and the macrocyclic dihydroxamic acid siderophore putrebactin (pbH2) in 1:1 H2O/CH3OH using triple quadrupole liquid chromatography-mass spectrometry (LC-MS-QQQ) (pH ≈ 4) showed two well-resolved peaks (tR(1) 10.85 min; tR(2) 14.27 min) using simultaneous detection modes (absorbance, 450 nm; selective ion monitoring, m/z 437) characteristic of the previously identified oxidoV(V) complex [V(V)O(pb)](+) ([M](+), m/zcalc 437.

Unsaturated macrocyclic dihydroxamic acid siderophores produced by Shewanella putrefaciens using precursor-directed biosynthesis.

To acquire iron essential for growth, the bacterium Shewanella putrefaciens produces the macrocyclic dihydroxamic acid putrebactin (pbH2; [M + H(+)](+), m/zcalc 373.2) as its native siderophore. The assembly of pbH2 requires endogenous 1,4-diaminobutane (DB), which is produced from the ornithine decarboxylase (ODC)-catalyzed decarboxylation of l-ornithine.

The variable hydroxamic acid siderophore metabolome of the marine actinomycete Salinispora tropica CNB-440.

The recently sequenced genome of the marine actinomycete Salinispora tropica CNB-440 revealed a high frequency of gene clusters which code for the biosynthesis of known and novel secondary metabolites. Of these metabolites, bioinformatics analysis predicted that S. tropica CNB-440 could potentially biosynthesize, as high affinity Fe(iii) ligands, siderophores from the hydroxamic acid desferrioxamine class (sid1 gene cluster) and the phenolate-thia(oxa)zoli(di)ne class (sid2 and sid4 gene clusters).

Directing the biosynthesis of putrebactin or desferrioxamine B in Shewanella putrefaciens through the upstream inhibition of ornithine decarboxylase.

To manage iron acquisition in an oxic environment, Shewanella putrefaciens produces the macrocyclic dihydroxamic acid putrebactin (PB) as its native siderophore. In this work, we have established the siderophore profile of S. putrefaciens in cultures augmented with the native PB precursor putrescine and in putrescine-depleted cultures.

Proteomics of Pseudomonas aeruginosa Australian epidemic strain 1 (AES-1) cultured under conditions mimicking the cystic fibrosis lung reveals increased iron acquisition via the siderophore pyochelin.

Pseudomonas aeruginosa is an opportunistic pathogen that is the major cause of morbidity and mortality in patients with cystic fibrosis (CF). While most CF patients are thought to acquire P. aeruginosa from the environment, person-to-person transmissible strains have been identified in CF clinics worldwide, and the molecular basis for transmissibility remains poorly understood.

Complexes formed in solution between vanadium(IV)/(V) and the cyclic dihydroxamic acid putrebactin or linear suberodihydroxamic acid.

An aerobic solution prepared from V(IV) and the cyclic dihydroxamic acid putrebactin (pbH(2)) in 1:1 H(2)O/CH(3)OH at pH = 2 turned from blue to orange and gave a signal in the positive ion electrospray ionization mass spectrometry (ESI-MS) at m/z(obs) 437.0 attributed to the monooxoV(V) species [V(V)O(pb)](+) ([C(16)H(26)N(4)O(7)V](+), m/z(calc) 437.3).

Studies of iron-uptake mechanisms in two bacterial species of the shewanella genus adapted to middle-range (Shewanella putrefaciens) or antarctic (Shewanella gelidimarina) temperatures.

Iron(III)-uptake mechanisms in bacteria indigenous to the Antarctic, which is the most Fe-deficient continent on Earth, have not been extensively studied. The cold-adapted, Antarctic bacterium, Shewanella gelidimarina, does not produce detectable levels of the siderophore, putrebactin, in the supernatant of Fe(III)-deprived cultures. This is distinct from the putrebactin-producing bacterium from the same genus, Shewanella putrefaciens, which is adapted to middle-range temperatures.

Zn(II)-dependent histone deacetylase inhibitors: suberoylanilide hydroxamic acid and trichostatin A.

Suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza) and trichostatin A (TSA) are inhibitors of the Zn(II)-dependent class I and class II histone deacetylases (HDACs), which are enzymes that operate in concert with histone acetyltransferases (HATs) to regulate the acetylation status of the epsilon-amino group of lysine residues of nucleosomal histones in chromatin. An increased level of histone acetylation resulting from the SAHA or TSA inhibition of Zn(II)-dependent HDACs relaxes the chromatin structure and upregulates transcription. The links made in the 1990s between the inhibition of HDAC activity and the suppression of tumor growth have brought the design of HDAC inhibitors (HDACi) to the forefront of oncology research.