Chemical Logic of Peptide Branching by Iterative Nonlinear Nonribosomal Peptide Synthetases.

Branch-point syntheses in nonribosomal peptide assembly are rare but useful strategies to generate tripodal peptides with advantageous hexadentate iron-chelating capabilities, as seen in siderophores. However, the chemical logic underlying the peptide branching by nonribosomal peptide synthetase (NRPS) often remains complex and elusive. Here, we review the common strategies for the biosynthesis of branched nonribosomal peptides (NRPs) and present our biochemical investigation on the NRPS-catalyzed assembly of fimsbactin A, a branched mixed-ligand siderophore produced by the human pathogenic strain .

Expanding the Substrate Selectivity of the Fimsbactin Biosynthetic Adenylation Domain, FbsH.

Nonribosomal peptide synthetases (NRPSs) produce diverse natural products including siderophores, chelating agents that many pathogenic bacteria produce to survive in low iron conditions. Engineering NRPSs to produce diverse siderophore analogs could lead to the generation of novel antibiotics and imaging agents that take advantage of this unique iron uptake system in bacteria. The highly pathogenic and antibiotic-resistant bacteria produces fimsbactin, an unusual branched siderophore with iron-binding catechol groups bound to a serine or threonine side chain.

Siderophore-dependent ferrichelatases.

Iron is a crucial secondary metabolite for bacterial proliferation, but its bioavailability under infection conditions is limited by the low solubility of ferric ion and the host's ability to sequester iron by protein chelation. In these iron limiting conditions, bacteria produce and secrete low molecular weight ferric ion chelators, siderophores, to scavenge host iron. Iron bound siderophores are recognized by surface displayed receptors and internalized by active transport preceding the liberation of the iron payload by reduction or cleavage of the siderophore.

Expanding the substrate selectivity of the fimsbactin biosynthetic adenylation domain, FbsH.

Nonribosomal peptide synthetases (NRPSs) produce diverse natural products including siderophores, chelating agents that many pathogenic bacteria produce to survive in low iron conditions. Engineering NRPSs to produce diverse siderophore analogs could lead to the generation of novel antibiotics and imaging agents that take advantage of this unique iron uptake system in bacteria. The highly pathogenic and antibiotic-resistant bacteria produces fimsbactin, an unusual branched siderophore with iron-binding catechol groups bound to a serine or threonine side chain.

Sequence-structure-function characterization of the emerging tetracycline destructase family of antibiotic resistance enzymes.

Tetracycline destructases (TDases) are flavin monooxygenases which can confer resistance to all generations of tetracycline antibiotics. The recent increase in the number and diversity of reported TDase sequences enables a deep investigation of the TDase sequence-structure-function landscape. Here, we evaluate the sequence determinants of TDase function through two complementary approaches: (1) constructing profile hidden Markov models to predict new TDases, and (2) using multiple sequence alignments to identify conserved positions important to protein function.