Towards the Native Binding Modes of Antibiotics that Target Lipid II

Abstract

The alarming rise of antimicrobial resistance (AMR) imposes severe burdens on healthcare systems and the economy worldwide, urgently calling for the development of new antibiotics. Antimicrobial peptides could be ideal templates for next‐generation antibiotics, due to their low propensity to cause resistance. An especially promising branch of antimicrobial peptides target lipid II, the precursor of the bacterial peptidoglycan network. To develop these peptides into clinically applicable compounds, detailed information on their pharmacologically relevant modes of action is of critical importance. Here we review the binding modes of a selection of peptides that target lipid II and highlight shortcomings in our molecular understanding that, at least partly, relate to the widespread use of artificial membrane mimics for structural studies of membrane‐active antibiotics. In particular, with the example of the antimicrobial peptide nisin, we showcase how the native cellular membrane environment can be critical for understanding of the physiologically relevant binding mode.

Real-Time Fluorescence Microscopy on Living E. coli Sheds New Light on the Antibacterial Effects of the King Penguin β-Defensin AvBD103b

“…If the cell envelope is somehow weakened, the internal pressure of the cytoplasm, normally counterbalanced by the pepdidoglycan layer, can no longer be contained. For example, AvBD103b could interfere with pepdidoglycan biosynthesis, as described for other AMPs through various mechanisms: (i) as proposed above to explain the halting of growth during Phase 1, AvBD103b could directly bind to peptidoglycan, like LL-37 does [43]; (ii) AvBD103b could bind one of the peptidoglycan precursors, as do some defensins from invertebrates [58][59][60] or other antimicrobials [61] with the essential precursor lipid II [62]; (iii) another possibility is that AvBD103b could interfere with fluid lipid micro-domains of the CM, then delocalizing essential peripheral membrane proteins, such as enzymes involved in pepdidoglycan biosynthesis. This phenomenon has been described for the hexapeptide RWRWRW [63] and for the cyclic lipopeptide daptomycin [64], which disturb the lipid II synthase MurG.…”

Rumo ao Estado Nativo com Ressonância Magnética Nuclear

“…Antibióticos que atuam por essa via são altamente eficazes e menos propícios ao desenvolvimento de resistência antimicrobiana [13] -por esta razão o lípido II é considerado o calcanhar de Aquiles das bactérias. Alguns exemplos de antibióticos que actuam por esta via são a plectasina, a teixobactina, a tridecaptina A1 e a nisina [14].…”

Protein resonance assignment by solid-state NMR based on 1H-detected 13C-based double-quantum spectroscopy at fast MAS

“…Solid-state nuclear magnetic resonance spectroscopy (SSNMR) is a powerful technique to study insoluble, aggregated or non-crystalline biomaterials, ranging from biopolymers ((Kelly et al 2020), (Zhao et al 2020),(Goldberga et al 2018)), carbohydrates ((El Hariri El Nokab and van der Wel 2020)), RNA (Ahmed et al 2020) or membranes (Dufourc 2021),(Mallikarjunaiah et al 2019) to larger systems such as protein complexes(Demers et al 2018) large proteins (Vasa et al 2018)(Schütz 2021)), protein-ligand interaction ((Vasa et al 2019)(Elkins and Hong 2019),(Medeiros-Silva et al 2019)), misfolded proteins (König et al 2019), amyloid (Tycko 2016)fibrils ((Jaroniec 2019),(Loquet et al 2018)), helical filaments (Habenstein et al 2019), viruses (Lecoq et al 2020), (Gupta et al 2020), (Lu et al 2020)), membrane proteins (McDermott 2009)(Tang et al 2013)(Mandala et al 2018) or whole cells ((Narasimhan et al 2020)). In the two past decades, structural investigation of biomolecules at atomic resolution by SSNMR has made dramatic analytical improvements with the introduction of direct proton ( 1 H) detection(Ishii et al 2001)(Reif et al 2001)(Paulson et al 2003)(Zhou et al 2009) combined with the use of magic-angle spinning (MAS) probes operating at fast frequencies(Nishiyama 2016)(Böckmann et al 2015)(Cala-De Paepe et al 2017)(Sternberg et al 2018)(Xue et al 2018)(Ishii et al 2018)(Schledorn et al 2020), nowadays commercially available at MAS frequency of 60-110 kHz.…”