Total Syntheses of Fimsbactin A and B and Their Stereoisomers to Probe the Stereoselectivity of the Fimsbactin Uptake Machinery in <i>Acinetobacter baumannii</i>

Kim, Soojeung; Lee, Haeun; Song, Woon; Kim, Hak Joong

doi:10.1021/acs.orglett.0c00790

Cited by 16 publications

(26 citation statements)

References 38 publications

(55 reference statements)

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“…baumannii clinical isolates possess the loci for acinetobactin and baumannoferrin biosynthesis and utilization, the individual contributions of these siderophores in vitro and in vivo have not been fully elucidated. Furthermore, although the synthesis pathway and structures of the fimsbactins have been characterized [ 43 , 55 , 56 ], their function in A . baumannii growth and survival has never been interrogated using strains that are specifically inactivated for fimsbactins biosynthesis.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

“…Indeed, whilst purified fimsbactins A and B are capable of supporting the iron-dependent growth of A . baumannii [ 55 , 56 ], it is not known how endogenous expression of this siderophore influences survival of the pathogen in vitro or in vivo .…”

Section: Introductionmentioning

confidence: 99%

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

2020

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“…Recently, a novel siderophore, cefiderocol (siderophore-cephalosporin conjugate), investigated in a subject suffering from kidney impairment, was found to be well tolerated as a treatment for multidrug-resistant strains [ 106 ]. Synthesis of fimsbactin A and B has also been studied recently, based on the synthesis routes as stereoisomeric analogues [ 107 ]. A gamma-lactam antimicrobial has been effectively tested upon MDR A. baumannii in the USA recently [ 108 ].…”

Section: Virulence Factorsmentioning

confidence: 99%

Virulence Potential and Treatment Options of Multidrug-Resistant (MDR) Acinetobacter baumannii

2021

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Acinetobacter baumannii is an opportunistic pathogen which is undoubtedly known for a high rate of morbidity and mortality in hospital-acquired infections. A. baumannii causes life-threatening infections, including; ventilator-associated pneumonia (VAP), meningitis, bacteremia, and wound and urinary tract infections (UTI). In 2017, the World Health Organization listed A. baumannii as a priority-1 pathogen. The prevalence of A. baumannii infections and outbreaks emphasizes the direct need for the use of effective therapeutic agents for treating such infections. Available antimicrobials, such as; carbapenems, tigecycline, and colistins have insufficient effectiveness due to the appearance of multidrug-resistant strains, accentuating the need for alternative and novel therapeutic remedies. To understand and overcome this menace, the knowledge of recent discoveries on the virulence factors of A. baumannii is needed. Herein, we summarized the role of various virulence factors, including; outer membrane proteins, efflux pumps, biofilm, penicillin-binding proteins, and siderophores/iron acquisition systems. We reviewed the recent scientific literature on different A. baumannii virulence factors and the effective antimicrobial agents for the treatment and management of bacterial infections.

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“… A. baumannii is known to produce and utilize three sets of siderophores, acinetobactins ( Fig. 1A , 1 and 2 ) ( 14 – 17 ), fimsbactins ( 3 ) ( 18 , 19 ), and baumannoferrins ( 4 ) ( 20 ) ( Fig. 1A ), although the presence of the genes responsible for their production and utilization differs across the strains ( 21 , 22 ).…”

Section: Introductionmentioning

confidence: 99%

Distinctive Roles of Two Acinetobactin Isomers in Challenging Host Nutritional Immunity

Kim

Song

et al. 2021

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Acinetobacter baumannii has acquired antibiotic resistance at an alarming rate, and it is becoming a serious threat to society, particularly due to the paucity of effective treatment options. Acinetobactin is a siderophore of Acinetobacter baumannii , responsible for active iron supply, and it serves as a key virulence factor to counter host nutritional immunity during infection.

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Total Syntheses of Fimsbactin A and B and Their Stereoisomers to Probe the Stereoselectivity of the Fimsbactin Uptake Machinery in Acinetobacter baumannii

Cited by 16 publications

References 38 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

Virulence Potential and Treatment Options of Multidrug-Resistant (MDR) Acinetobacter baumannii

Distinctive Roles of Two Acinetobactin Isomers in Challenging Host Nutritional Immunity

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