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1. In Vitro Reconstitution of Fimsbactin Biosynthesis from Acinetobacter baumannii

   https://doi.org/10.1021/acschembio.2c00573  

   Yang, Jinping ; Wencewicz, Timothy A. ( July 2022 , ACS Chemical Biology)

   He, Chuan ; Seyedsayamdost, Mohammed R. (Ed.)

   Siderophores produced via non-ribosomal peptide synthetase (NRPS) pathways serve as critical virulence factors for many pathogenic bacteria. An improved knowledge of siderophore biosynthesis guides the development of inhibitors, vaccines, and other therapeutic strategies. Fimsbactin A is a mixed ligand siderophore derived from human pathogenic Acinetobacter baumannii that contains phenolate-oxazoline, catechol, and hydroxamate metal chelating groups branching from a central L-Ser tetrahedral unit via amide and ester linkages. Fimsbactin A is derived from two molecules of L-Ser, two molecules of 2,3-dihydroxybenzoic acid (DHB), and one molecule of L-Orn and is a product of the fbs biosynthetic operon. Here, we report the complete in vitro reconstitution of fimsbactin A biosynthesis in a cell-free system using purified enzymes. We demonstrate the conversion of L-Orn to N1-acetyl-N1-hydroxy-putrescine (ahPutr) via ordered action of FbsJ (decarboxylase), FbsI (flavin N-monooxygenase), and FbsK (N-acetyltransferase). We achieve conversion of L-Ser, DHB, and L-Orn to fimsbactin A using FbsIJK in combination with the NRPS modules FbsEFGH. We also demonstrate chemoenzymatic conversion of synthetic ahPutr to fimsbactin A using FbsEFGH and establish the substrate selectivity for the NRPS adenylation domains in FbsH (DHB) and FbsF (L-Ser). We assign a role for the type II thioesterase FbsM in producing the shunt metabolitemore »2-(2,3-dihydroxyphenyl)-4,5-dihydrooxazole-4-carboxylic acid (DHB-oxa) via cleavage of the corresponding thioester intermediate that is tethered to NRPS peptidyl carrier domains during biosynthetic assembly. We propose a mechanism for branching NRPS-derived peptides via amide and ester linkages via the dynamic equilibration of N-DHB-Ser and O-DHB-Ser thioester intermediates via hydrolysis of DHB-oxa thioester intermediates. We also propose a genetic signature for NRPS ‘branching’ in the presence of a terminating C-T-C motif (FbsG).« less
2. Total Synthesis of an All-1,2- cis -Linked Repeating Unit from the Acinetobacter baumannii D78 Capsular Polysaccharide

   https://doi.org/10.1021/acs.orglett.2c01034  

   Njeri, Dancan K. ; Ragains, Justin R. ( May 2022 , Organic Letters)
3. Rigid Oxazole Acinetobactin Analog Blocks Siderophore Cycling in Acinetobacter baumannii

   https://doi.org/10.1021/acsinfecdis.7b00146  

   Bohac, Tabbetha J. ; Shapiro, Justin A. ; Wencewicz, Timothy A. ( October 2017 , ACS Infectious Diseases)
4. Fimsbactin and Acinetobactin Compete for the Periplasmic Siderophore Binding Protein BauB in Pathogenic Acinetobacter baumannii

   https://doi.org/10.1021/acschembio.8b01051  

   Bohac, Tabbetha J. ; Fang, Luting ; Giblin, Daryl E. ; Wencewicz, Timothy A. ( March 2019 , ACS Chemical Biology)
5. Ultrafast Structural Dynamics of BlsA, a Photoreceptor from the Pathogenic Bacterium Acinetobacter baumannii

   https://doi.org/10.1021/jz4023738  

   Brust, Richard ; Haigney, Allison ; Lukacs, Andras ; Gil, Agnieszka ; Hossain, Shahrier ; Addison, Kiri ; Lai, Cheng-Tsung ; Towrie, Michael ; Greetham, Gregory M. ; Clark, Ian P. ; et al ( January 2014 , The Journal of Physical Chemistry Letters)