Key Structural Elements for Cellular Uptake of Acinetobactin, a Major Siderophore of <i>Acinetobacter baumannii</i>

Song, Woon; Jeong, Dawa; Kim, Jimin; Lee, Min Wook; Oh, Man Hwan; Kim, Hak Joong

doi:10.1021/acs.orglett.6b03671

Cited by 28 publications

(32 citation statements)

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“…The nature of one of the main siderophore molecules taken up by A. baumannii is important, both for understanding the physiology of this significant pathogen and for the rational design of the so-called ‘trojan horse’ antibiotics. Conflicting reports are extant in the literature as to whether the molecule which is taken up is preacinetobactin or acinetobactin (Song et al, 2017; Shapiro and Wencewicz, 2017). As our own experiments have shown, small amounts of impurities that are hard to eliminate coupled to ready conversion of preacinetobactin to acinetobactin poses significant technical challenges in resolving this problem.…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, one of the oxygens and a carbon of catechol seem plausible candidates for expansion (Figure 4b). Shapiro and Wencewicz (2017) and Song et al (2017) reported important indications about the role of the different portions of both ligands by comparing the biological activity of multiple derivatives and checking complex formation through UV-vis spectroscopy. These studies confirm the 2-OH of preacinetobactin is essential but changes at the 3 and 5 positions of the catechol are well tolerated (no information on the four position was reported).…”

Section: Resultsmentioning

confidence: 99%

“…Acinetobactin is synthesized as a precursor, preacinetobactin, which rearranges non-enzymatically and irreversibly at pH >7 to give acinetobactin (Figure 1A) (Sattely and Walsh, 2008; Wuest et al, 2009; Shapiro and Wencewicz, 2016). There have been different reports on whether acinetobactin or preacinetobactin or both are transported into the bacteria (Song et al, 2017; Shapiro and Wencewicz, 2017) complicating rational design. The A. baumannii outer-membrane transporter protein, BauA, that recognises this siderophore has itself been identified as a vaccine candidate (Esmaeilkhani et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Preacinetobactin not acinetobactin is essential for iron uptake by the BauA transporter of the pathogen Acinetobacter baumannii

Moynié

Serra

Scorciapino

et al. 2018

eLife

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New strategies are urgently required to develop antibiotics. The siderophore uptake system has attracted considerable attention, but rational design of siderophore antibiotic conjugates requires knowledge of recognition by the cognate outer-membrane transporter. Acinetobacter baumannii is a serious pathogen, which utilizes (pre)acinetobactin to scavenge iron from the host. We report the structure of the (pre)acinetobactin transporter BauA bound to the siderophore, identifying the structural determinants of recognition. Detailed biophysical analysis confirms that BauA recognises preacinetobactin. We show that acinetobactin is not recognised by the protein, thus preacinetobactin is essential for iron uptake. The structure shows and NMR confirms that under physiological conditions, a molecule of acinetobactin will bind to two free coordination sites on the iron preacinetobactin complex. The ability to recognise a heterotrimeric iron-preacinetobactin-acinetobactin complex may rationalize contradictory reports in the literature. These results open new avenues for the design of novel antibiotic conjugates (trojan horse) antibiotics.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Preacinetobactin not acinetobactin is essential for iron uptake by the BauA transporter of the pathogen Acinetobacter baumannii

Moynié

Serra

Scorciapino

et al. 2018

eLife

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“…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%

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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“…Other virulence factors encompass iron acquisition system (basD), phospholipase D (slpD), surface antigen protein A (surA), and penicillin-binding protein G (bpbG) [7,8]. Therefore, the present study aimed to identify nine diverse virulence genes in A. baumannii isolates isolated from patients with pneumonia hospitalized in the Intensive Care Unit (ICU) of Imam Khomeini Hospital, Tehran, Iran.…”

Section: Introductionmentioning

confidence: 99%

Prevalence Determination of Virulence Related and Biofilm Formation Genes in Acinetobacter baumannii Isolates from Clinical Respiratory Samples in Imam Khomeini Hospital, Tehran, Iran in 2018

مظفری¹,

میرکلانتری²,

کلانی³

et al. 2021

Iran J Med Microbiol

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Background and Aim: Acinetobacter baumannii is considered to be a re-emerging causative agent of nosocomial infections. There is a significant relation between pathogenicity of this bacterium and the numerous virulence factors. The purpose of this study was to investigate nine virulence factor genes in A. baumannii isolates derived from hospitalized patients. Materials and Methods:A total of 50 A. baumannii isolates were recovered from patients with pneumonia in Imam Khomeini Hospital, Tehran, Iran. Following biochemical and microbiological identification of the bacteria, Multiplex PCR was performed for basD, plD, csuA genes, surA, pbpG, bfmR genes, and bap, ompA genes using specific sets of primers which were specifically designed for this study. The espA was identified separately by a Uniplex PCR assay. All amplified DNA fragments were sequenced for the products' confirmation.Results: Among the 50 clinical isolates of A. baumannii studied, bfmR and pbpG genes were reported in all samples (100%), bap, plD, surA, and csuA genes were collected from 49 samples (98%), 48 (96%) of these isolates had ompA and basD genes, and espA gene was observed in only five isolates (10%). Conclusion:According to this study results, virulence factors genes in clinical A. baumannii have a prevalence rate more than 90%. Additionally, the high incidence rate of those genes related to biofilm formation indicates that most clinical strains have the ability to form biofilm structures.

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Key Structural Elements for Cellular Uptake of Acinetobactin, a Major Siderophore of Acinetobacter baumannii

Cited by 28 publications

References 24 publications

Preacinetobactin not acinetobactin is essential for iron uptake by the BauA transporter of the pathogen Acinetobacter baumannii

Preacinetobactin not acinetobactin is essential for iron uptake by the BauA transporter of the pathogen Acinetobacter baumannii

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

Prevalence Determination of Virulence Related and Biofilm Formation Genes in Acinetobacter baumannii Isolates from Clinical Respiratory Samples in Imam Khomeini Hospital, Tehran, Iran in 2018

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