4,7-Diaminoisoindoline-1,3-dione

Gnanasekaran, Krishna Kumar; Rivera, Mario; Bunce, Richard A.

doi:10.1080/00304948.2018.1462072

Cited by 1 publication

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“…Fragment screening followed by efforts to cocrystallize the fragment hits with BfrB produced the X-ray crystal structure of BfrB in complex with 4-aminoisoindoline-1,3-dione ( 8 ) binding at the Bfd-binding site . The cocrystal structure informed a strategy for fragment growth that produced a series of 4-(benzylamino)- and 4-((3-phenylpropyl)amino)isoindoline-1,3-dione analogues represented by 11 and 16 (Table ), which are derivatives of 8 with −(CH 2 )– and −(CH 2 ) 3 – linkers, respectively. , These analogues were shown to selectively bind BfrB at the Bfd binding site and to elicit a growth defect in P. aeruginosa planktonic cell cultures . To increase the binding affinity of 11 and 16 for BfrB we looked for information in the available structural data.…”

Section: Results and Discussionmentioning

confidence: 99%

Small Molecule Inhibitors of the Bacterioferritin (BfrB)–Ferredoxin (Bfd) Complex Kill Biofilm-Embedded Pseudomonas aeruginosa Cells

et al. 2020

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Bacteria depend on a well-regulated iron homeostasis to survive adverse environments. A key component of the iron homeostasis machinery is the compartmentalization of Fe 3+ in bacterioferritin and its subsequent mobilization as Fe 2+ to satisfy metabolic requirements. In Pseudomonas aeruginosa Fe 3+ is compartmentalized in bacterioferritin (BfrB), and its mobilization to the cytosol requires binding of a ferredoxin (Bfd) to reduce the stored Fe 3+ and release the soluble Fe 2+ . Blocking the BfrB-Bfd complex in P. aeruginosa by deletion of the bfd gene triggers an irreversible accumulation of Fe 3+ in BfrB, concomitant cytosolic iron deficiency and significant impairment of biofilm development. Herein we report that small molecules developed to bind BfrB at the Bfd binding site block the BfrB-Bfd complex, inhibit the mobilization of iron from BfrB in P. aeruginosa cells, elicit a bacteriostatic effect on planktonic cells, and are bactericidal to cells embedded in mature biofilms.

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