Pyoverdine

Pyoverdines^[1] (alternatively, and less commonly, spelled as pyoverdins) are fluorescent siderophores produced by certain pseudomonads.^[2][3] Pyoverdines are important virulence factors, and are required for pathogenesis in many biological models of infection. Their contributions to bacterial pathogenesis include providing a crucial nutrient (i.e., iron), regulation of other virulence factors (including exotoxin A and the protease PrpL),^[4] supporting the formation of biofilms,^[5] and are increasingly recognized for having toxicity themselves.^[6][7][8]

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Pyoverdine

Names
Other names Pyoverdin
Identifiers
3D model (JSmol)	Interactive image
ChEBI	family: CHEBI:84046
PubChem CID	57012495
InChI InChI=1S/C56H88N18O22/c1-27(79)43-53(91)61-15-4-3-8-31(46(84)65-34(11-7-19-73(96)26-78)49(87)70-44(28(2)80)54(92)71-43)64-47(85)33(10-6-18-72(95)25-77)67-50(88)36(23-75)68-48(86)32(9-5-16-62-56(58)59)66-51(89)37(24-76)69-52(90)38-14-17-60-45-35(63-42(83)13-12-30(57)55(93)94)20-29-21-40(81)41(82)22-39(29)74(38)45/h20-22,25-28,30-34,36-38,43-45,60,75-76,79-82,95-96H,3-19,23-24,57H2,1-2H3,(H,61,91)(H,63,83)(H,64,85)(H,65,84)(H,66,89)(H,67,88)(H,68,86)(H,69,90)(H,70,87)(H,71,92)(H,93,94)(H4,58,59,62) Key: QIRRYPHVUMPBDX-UARRTFJPSA-N
SMILES CC(C1C(=O)NC(C(=O)NCCCCC(C(=O)NC(C(=O)N1)CCCN(C=O)O)NC(=O)C(CCCN(C=O)O)NC(=O)C(CO)NC(=O)C(CCCN=C(N)N)NC(=O)C(CO)NC(=O)C2CCNC3N2C4=CC(=C(C=C4C=C3NC(=O)CCC(C(=O)O)N)O)O)C(C)O)O
Properties
Chemical formula	C56H88N18O22
Molar mass	1365.424 g·mol−1
Appearance	Solid
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Y verify (what is YN ?) Infobox references

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Pyoverdines have also been investigated as "Trojan Horse" molecules for the delivery of antimicrobials to otherwise resistant bacterial strains, as chelators that can be used for bioremediation of heavy metals, and as fluorescent reporters used to assay for the presence of iron and potentially other metals.^[9]

Due to their bridging the gaps between pathogenicity, iron metabolism, and fluorescence, pyoverdines have piqued the curiosity of scientists around the world for over 100 years.^{[citation needed]}

Like most siderophores, pyoverdine is synthesized and secreted into the environment when the microorganism that produces it detects that intracellular iron concentrations have fallen below a preset threshold. Although iron is the fourth-most abundant element in the Earth's crust, solubility of biologically relevant iron compounds is exceedingly low, and is generally insufficient for the needs of most (but not all) microorganisms. Siderophores, which are typically quite soluble and have exceptionally high avidity for iron (III) (the avidity of some siderophores for iron exceeds 10⁴⁰ M^-1 and many of the strongest avidities ever observed in nature are exhibited by siderophores for iron), help increase bioavailability of iron by pulling it into aqueous solution.

In addition to this role, pyoverdine has a number of other functions, including regulating virulence,^[4][5] limiting the growth of other bacterial species (and serving as a sort of antimicrobial) by limiting iron availability, and sequestering other metals and preventing their toxicity.

Although many (>100) forms of pyoverdine have been isolated and studied, they all have certain characteristics in common. Each pyoverdine molecule has three parts: a dihydroxyquinoline core, a 6-14 amino acid peptide that varies among strains, and a side chain (usually composed of a 4-5 carbon α-ketoacid from the Krebs/citric acid cycle). The core of pyoverdine is responsible for several of its properties, including its well-known yellowish color and fluorescence.

Pyoverdine has been reported to be required for virulence in a variety of disease models, including C. elegans and various models of murine infection (e.g., burn models, pneumonia models, etc.).^{[6][15][25][26]}

As noted above, pyoverdine contributes in several fashions to general virulence, including regulating the production of itself, exotoxin A (which stalls translation), and the protease PrpL.^[4] There is also evidence that, although not essential for its formation, pyoverdine contributes to the production and development of biofilms that are important for virulence.^[5]

Finally, pyoverdine is associated with several types of toxicity in its own right. In 2001, Albesa and colleagues reported that pyoverdine purified from a strain of P. fluorescens exhibited profound cytotoxicity to mammalian macrophages and that this effect was at least partially dependent upon reactive oxygen species.^[27] Later, Kirienko and colleagues determined that pyoverdine is both necessary and sufficient for killing C. elegans, that enters host cells, destabilizes mitochondrial dynamics, and induces a hypoxic response.^[6][7] Exposure triggers a response that is consistent with hypoxia that depends on the HIF-1 protein, suggesting that the host perceives a condition where it lacks the molecular tools for generating ATP (generally, iron, oxygen, and cellular reducing equivalents).^[6][7]

Once pyoverdine is secreted, it diffuses freely in the environment. Iron-bound pyoverdine (also known as ferripyoverdine) can be taken up by any bacterial cell with the appropriate receptor, although this varies between strains.^[28] Importantly, this creates a common good which can be exploited by 'cheaters' which retain the ability to use pyoverdine but have stopped making it. Since pyoverdine production is energetically costly, this can create a fitness advantage in cells that are not synthesizing it.^{[29][30][31][32]} Consequently, pyoverdine has become a model trait to study microbial cooperation and exploitation.^[33][34]

In P. aeruginosa, pyoverdine non-producing “cheat” bacteria have been shown to i) evolve readily from a producing ancestor;^[35] and ii) outcompete cooperating strains in mixed culture in a density- and frequency-dependent manner.^[36][37] Since pyoverdine usage relies on passive diffusion and pyoverdine production is metabolically costly, environmental conditions are known to influence the likelihood of successful exploitation. The competitive advantage of pyoverdine non-producers over producers in mixed culture was shown to be maximized when environments are well-mixed and molecules diffuse readily (low spatial structure) and when the costs and benefits of pyoverdine production are high, i.e. when iron is strongly limited.^[31][38] Most studies on pyoverdine cooperation and cheating have been conducted using clinical isolates, but siderophore exploitation was recently also demonstrated in natural Pseudomonas isolates from non-clinical samples.^[39][40]

Currently, no widespread and systematic nomenclature is used to differentiate pyoverdine structures. A system was proposed in 1989,^[41] consisting of Pyoverdine Type I, Type IIa, Type IIb, and Type III. At the time, only a few pyoverdine structures were known, and it was anticipated that much less variation would occur than has been seen. As a consequence of the tremendous heterogeneity observed in the peptide backbone, and the observation of congeners (pyoverdines from a single strain differing only in their ketoacid portions), nomenclature of pyoverdines remains rather tenuous and no single system has garnered universal acceptance.

• 1850s: Sédillot notes a blue-green discharge from surgical wound dressings.
• 1860: Pyoverdine (although not so named) was extracted from wound dressings by Fordos.
• 1862: Lucke associates pyoverdine with bacilli observed under microscope.
• 1882: Pseudomonas aeruginosa grown for first time in pure culture by Carle Gessard, reported in "On the Blue and Green Coloration of Bandages". Gessard names the organism Bacillus aeruginosa, after "aerugo", the Latin word for verdigris.
• 1889: Bouchard observes that injection of a rabbit infected with Bacillus anthracis (causative agent of anthrax) with P. aeruginosa prevents formation of anthrax.
• 1889: Bouchard discovers that pyoverdine fluoresces under ultraviolet light.
• 1948, 1952: First observations that concentrations of iron and pyoverdine are reciprocal.
• 1978: Meyer and colleagues make first demonstration of role for pyoverdine in iron acquisition.
• 1980s–1990s: First structures and regulation of proverdine worked out
• 1999: First determination that pyoverdine fluorescence is quenched by iron binding.

A compound related to pyoverdine, called pseudoverdine (formally known as 3-formylamino-6,7-dihydroxycoumarin) is also produced by some fluorescent Pseudomonads.^[42] It is thought that pseudoverdine and pyoverdine may arise from a common precursor, 2,4,5-trihydroxyphenylalanine, which may condense with L-2,4-diaminobutyric acid to initiate pyoverdine production.^[42]

Pseudoverdine is relatively similar to pyoverdine in its fluorescence and other spectroscopic properties, and its ability to chelate ferric iron, albeit at much lower affinity.^[42] Unlike pyoverdine, it is incapable of transporting iron into cells, likely due to the absence of the peptide chain.^[42] Another dissimilarity is that pseudoverdine does not appear to be regulated by the same processes as pyoverdine.^[42]