Probing key elements of teixobactin–lipid II interactions in membranes

Wen, Po‐Chao; Vanegas, Juan M.; Rempe, Susan; Tajkhorshid, Emad

doi:10.1039/c8sc02616e

Cited by 23 publications

(27 citation statements)

References 57 publications

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“…In the bound state, the C‐terminal macrocyclic part of teixobactin presumably complexes lipid II, whereas the N‐terminal residues, which are disordered in the unbound state, adopt a β‐strand structure involved in peptide aggregation. Such a binding mode is in line with recent long MD simulations of the teixobactin ⋅ lipid II complex in membranes . Interestingly, the solid‐state NMR study also strongly suggests that the pentapeptide or the sugar moieties of lipid II play a critical role for the binding mode and aggregation of teixobactin.…”

Section: Peptide Antibiotics That Bind Lipid IIsupporting

confidence: 85%

Towards the Native Binding Modes of Antibiotics that Target Lipid II

et al. 2019

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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.

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Section: Peptide Antibiotics That Bind Lipid IIsupporting

confidence: 85%

Towards the Native Binding Modes of Antibiotics that Target Lipid II

et al. 2019

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“…Interestingly, this is very similar to the recently resolved X-ray structure of another lipid II's PPi binder -depsipeptide teixobactin analogue, which coordinated chloride anion by five NH groups 41 . Moreover, the similarity of nisin and teixobactin binding motif to lipid II was revealed in a computer experiment 42 .…”

Section: Conformational Dynamics Of Nisin and Its Recognition Module mentioning

confidence: 99%

Environmental and dynamic effects explain how nisin captures membrane-bound lipid II

Panina

Крылов

Nolde

et al. 2020

Sci Rep

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Antibiotics (AB) resistance is a major threat to global health, thus the development of novel AB classes is urgently needed. Lantibiotics (i.e. nisin) are natural compounds that effectively control bacterial populations, yet their clinical potential is very limited. Nisin targets membrane-embedded cell wall precursor-lipid II-via capturing its pyrophosphate group (PPi), which is unlikely to evolve, and thus represents a promising pharmaceutical target. Understanding of exact molecular mechanism of initial stages of membrane-bound lipid II recognition by water-soluble nisin is indispensable. Here, using molecular simulations, we demonstrate that the structure of lipid II is determined to a large extent by the surrounding water-lipid milieu. In contrast to the bulk solvent, in the bilayer only two conformational states remain capable of nisin binding. In these states PPi manifests a unique arrangement of hydrogen bond acceptors on the bilayer surface. Such a "pyrophosphate pharmacophore" cannot be formed by phospholipids, which explains high selectivity of nisin/lipid II recognition. Similarly, the "recognition module" of nisin, being rather flexible in water, adopts the only stable conformation in the presence of PPi analogue (which mimics the lipid II molecule). We establish the "energy of the pyrophosphate pharmacophore" approach, which effectively distinguishes nisin conformations that can form a complex with PPi. Finally, we propose a molecular model of nisin recognition module/lipid II complex in the bacterial membrane. These results will be employed for further study of lipid II targeting by antimicrobial (poly)cyclic peptides and for design of novel AB prototypes. The widespread misuse of antibiotics (AB) results in fast development of resistance by bacteria, which presents a growing threat to global health. Discovery of new classes of antibacterial agents with alternative mode of action along with grasp of these mechanisms present the primary scientific challenges. There is a class of lanthionine-containing antimicrobial peptides (AMPs) referred to as lantibiotics, which possesses medicinal potential. Nisin, the most studied lantibiotic, was known even before A. Fleming's penicillin discovery 1. Although nisin has never been used in clinical practice due to its poor pharmacokinetics, it has been widely utilized as a food preservative since 1953 with no evidence of any resistance development 2-4. Nisin is a 34-amino acid peptide produced by certain strains of Lactococcus Lactis. Following the ribosomal synthesis, nisin prepeptide undergoes significant post-translational modifications, including proteolytic removal of a leader peptide 5 and introduction of atypical amino acids, resulting in five lanthionine rings and three unsaturated residues (Fig. 1A) 6. NMR studies of nisin and its major degradation products under various conditions revealed that the molecule is highly flexible in aqueous solution and consists of two structural domains: an amphiphilic N-terminal fragment including lanthionine rings A, B a...

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“…Similarly teixobactin, the only new class of drug discovered in the last 33 years [119], has high efficacy against Gram-positive bacteria but lacks any Gram-negative antibacterial activity. The target for teixobactin is lipid II [120,121] an essential precursor for both Gram-positive and Gram-negative cell wall synthesis. Hence, the Gram-positive selective activity of teixobactin could most probably be attributed to inability to reach its target in Gram-negatives; this issue could potentially be solved by co-administration of an OM permeabiliser.…”

Section: Discussionmentioning

confidence: 99%

Reversing resistance to counter antimicrobial resistance in the World Health Organisation’s critical priority of most dangerous pathogens

Venter

2019

Bioscience Reports

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The speed at which bacteria develop antimicrobial resistance far outpace drug discovery and development efforts resulting in untreatable infections. The World Health Organisation recently released a list of pathogens in urgent need for the development of new antimicrobials. The organisms that are listed as the most critical priority are all Gram-negative bacteria resistant to the carbapenem class of antibiotics. Carbapenem resistance in these organisms is typified by intrinsic resistance due to the expression of antibiotic efflux pumps and the permeability barrier presented by the outer membrane, as well as by acquired resistance due to the acquisition of enzymes able to degrade β-lactam antibiotics. In this perspective article we argue the case for reversing resistance by targeting these resistance mechanisms – to increase our arsenal of available antibiotics and drastically reduce antibiotic discovery times – as the most effective way to combat antimicrobial resistance in these high priority pathogens.

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Probing key elements of teixobactin–lipid II interactions in membranes

Abstract: Two binding poses of the teixobactin–lipid II complex were captured with MD simulations at the membrane surface.

Cited by 23 publications

References 57 publications

Towards the Native Binding Modes of Antibiotics that Target Lipid II

Towards the Native Binding Modes of Antibiotics that Target Lipid II

Environmental and dynamic effects explain how nisin captures membrane-bound lipid II

Reversing resistance to counter antimicrobial resistance in the World Health Organisation’s critical priority of most dangerous pathogens

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