Current biochemical understanding regarding the metabolism of acinetobactin, the major siderophore of the human pathogen <i>Acinetobacter baumannii</i>, and outlook for discovery of novel anti-infectious agents based thereon

Song, Woon; Kim, Hak Joong

doi:10.1039/c9np00046a

Cited by 27 publications

(32 citation statements)

References 49 publications

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“…baumannii ATCC 17978 genome. The disrupted genes include basG , encoding a putative histidine decarboxylase predicted to synthesize histamine as an essential precursor molecule to acinetobactin biosynthesis [ 44 , 62 ], bfnL , encoding a putative acetyltransferase predicted to facilitate the conversion of N 3 -hydroxy-1,3-diaminopropane to N 3 -decanoyl-hydroxy-1,3-diaminopropane as an early step in baumannoferrin biosynthesis [ 42 ], and fbsE , encoding a putative nonribosomal peptide synthase (NRPS) and the first part of the multi-modular unit required to assemble fimsbactins [ 43 ].…”

Section: Resultsmentioning

confidence: 99%

“…These findings support an often stated, but not fully substantiated assertion that acinetobactin is the major, or most important, siderophore produced by A . baumannii [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

“…baumannii . Importantly, the essential features required for iron coordination by, and cellular uptake of acinetobactin have been identified, along with a promising sites for the conjugation of an antibiotic [ 38 , 44 , 91 ]. Interestingly, in assessing the development of resistance to another experimental sideromycin (BAL30072), A .…”

Section: Discussionmentioning

confidence: 99%

“…Acinetobactin is often referred to as being the major siderophore produced by A . baumannii , largely due to the high degree of conservation of the encoding locus amongst Acinetobacter clinical isolates [ 30 , 31 , 44 ]. The siderophore exists as two pH-dependent isomers, pre-acinetobactin which is released by the bacteria and is prevalent under acidic conditions, and acinetobactin which is favored under neutral and basic conditions [ 38 , 39 , 45 ].…”

Section: Introductionmentioning

confidence: 99%

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Acinetobacter baumannii can use multiple siderophores for iron acquisition, but only acinetobactin is required for virulence

2020

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Acinetobacter baumannii is an emerging pathogen that poses a global health threat due to a lack of therapeutic options for treating drug-resistant strains. In addition to acquiring resistance to last-resort antibiotics, the success of A . baumannii is partially due to its ability to effectively compete with the host for essential metals. Iron is fundamental in shaping host-pathogen interactions, where the host restricts availability of this nutrient in an effort to curtail bacterial proliferation. To circumvent restriction, pathogens possess numerous mechanisms to obtain iron, including through the use of iron-scavenging siderophores. A . baumannii elaborates up to ten distinct siderophores, encoded from three different loci: acinetobactin and pre-acinetobactin (collectively, acinetobactin), baumannoferrins A and B, and fimsbactins A-F. The expression of multiple siderophores is common amongst bacterial pathogens and often linked to virulence, yet the collective contribution of these siderophores to A . baumannii survival and pathogenesis has not been investigated. Here we begin dissecting functional redundancy in the siderophore-based iron acquisition pathways of A . baumannii . Excess iron inhibits overall siderophore production by the bacterium, and the siderophore-associated loci are uniformly upregulated during iron restriction in vitro and in vivo . Further, disrupting all of the siderophore biosynthetic pathways is necessary to drastically reduce total siderophore production by A . baumannii , together suggesting a high degree of functional redundancy between the metabolites. By contrast, inactivation of acinetobactin biosynthesis alone impairs growth on human serum, transferrin, and lactoferrin, and severely attenuates survival of A . baumannii in a murine bacteremia model. These results suggest that whilst A . baumannii synthesizes multiple iron chelators, acinetobactin is critical to supporting growth of the pathogen on host iron sources. Given the acinetobactin locus is highly conserved and required for virulence of A . baumannii , designing therapeutics targeting the biosynthesis and/or transport of this siderophore may represent an effective means of combating this pathogen.

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Section: Resultsmentioning

confidence: 99%

“…These findings support an often stated, but not fully substantiated assertion that acinetobactin is the major, or most important, siderophore produced by A . baumannii [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acinetobacter baumannii can use multiple siderophores for iron acquisition, but only acinetobactin is required for virulence

2020

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“…Columns are virulence genes identified. b. P. putida KT2440 bauABCDE genetic context annotated according Pseudomonas Genome Database (www.pseudomonas.com) and Song and Kim (2020).…”

Section: Resultsmentioning

confidence: 99%

Phylogenetic and population structure analyses uncover pervasive misclassification and help assessing the biosafety of Pseudomonas alloputida for biotechnological applications

Araujo

Henaut-Jacobs

Franco

et al. 2020

Preprint

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Pseudomonads inhabit a variety of environments. Pseudomonas putida is a saprophytic soil bacterium, known to bioremediate toxic compounds and to promote plant growth. Despite the ability to occupy different niches, the population structure of P. putida remains unclear. Here, we report its population structure for the first time. We retrieved 11,025 Pseudomonas genomes and used P. putida KT2440 as a type strain to define P. putida. We found that 90 of the 138 deposited P. putida genomes were misclassified, including some reference genomes. The population structure of P. putida is composed of at least 7 clonal complexes (CCs). Clinical isolates are not restricted to a specific CC and acquired resistance genes are present at low frequency in plasmids from clinical isolates. Virulence profiles support the potential of CC7 members to outcompete other plant or human pathogens through a type VI secretion system. P. putida lacks key genes for indole-3-acetic acid production, indicating an incomplete or non-functional pathway. Finally, we found that horizontal gene transfer had an important role in shaping the ability of P. putida to bioremediate aromatic compounds such as toluene. Our results provide the grounds to understand P. putida genetic diversity and its safety for environmental applications.

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The role of quorum sensing, biofilm formation, and iron acquisition as key virulence mechanisms in Acinetobacter baumannii and the corresponding anti-virulence strategies

Law

Tan

2022

Microbiological Research

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Current biochemical understanding regarding the metabolism of acinetobactin, the major siderophore of the human pathogen Acinetobacter baumannii, and outlook for discovery of novel anti-infectious agents based thereon

Abstract: This Highlight covers recently unveiled biochemical aspects the acinetobactin metabolism, a central iron acquisition mechanism of Acinetobacter baumannii, in addition to various efforts for therapeutic application of these findings.

Cited by 27 publications

References 49 publications

Acinetobacter baumannii can use multiple siderophores for iron acquisition, but only acinetobactin is required for virulence

Acinetobacter baumannii can use multiple siderophores for iron acquisition, but only acinetobactin is required for virulence

Phylogenetic and population structure analyses uncover pervasive misclassification and help assessing the biosafety of Pseudomonas alloputida for biotechnological applications

The role of quorum sensing, biofilm formation, and iron acquisition as key virulence mechanisms in Acinetobacter baumannii and the corresponding anti-virulence strategies

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