Biophysical studies of bacterial proteins; can we address antibiotic resistance? [article]

Subrata Paul, University Of Calgary, University Of Calgary, Hans Vogel
2017
It is forecast that the single biggest challenge to medical care in the twenty-first century will be the control of antibiotic resistant bacteria, including multidrug resistant strains. Although numerous factors are associated with the rapid emergence of pathogen resistance, the limited number of core structures of currently used antibiotics is one of the reasons for this development. Unlike other conventional antibiotics, the recently discovered class of lipopeptide antibiotics consists of a
more » ... clic peptide head group with an acyl chain that are synthesized by a non-ribosomal peptide synthetase in association with an acyl carrier protein (ACP). This dissertation presents the solution structure of an ACP, LipD that is involved in the acylation of the lipopeptide antibiotic friulimicin. Enhanced stability of holo-LipD (LipD with the phosphopantetheine group attached) was observed through biophysical investigations. This may originate from a subtle change in the helix angles, required for the attachment of the acyl chain. Moreover, interaction studies of ACPs with antimicrobial peptides (AMPs) revealed that bacterial ACPs can be novel targets for AMPs and that this may perturb the fatty acid synthesis to abrogate the pathogenesis of recalcitrant pathogens such as Pseudomonas aeruginosa. We also investigated the ligand binding properties of two selected periplasmic binding proteins (PBP). Understanding the mechanisms by which PBPs can bind and release various ligands has implications for designing biosensors and developing therapeutic compounds that will perturb the pathways mediated by PBPs. Detailed biophysical studies of the Escherichia.coli ferric citrate binding PBP, FecB, revealed that it could form complexes with a wide variety of different tricarboxylic acid-iron complexes. Moreover unexpectedly FecB was found to bind apo-citrate and other iron-free tricarboxylic acids with great avidity. Information regarding the plasticity of substrate binding by FecB will allow us to design new strategies to overcome bacte [...]
doi:10.11575/prism/25138 fatcat:qzmqmv6povcixku5or2r3kruxa