Visualizing the mode of action and supramolecular assembly of teixobactin analogues in <i>Bacillus subtilis</i>

Morris, Michael A.; Vallmitjana, Alexander; Grein, Fabian; Schneider, Tanja; Arts, Melina; Jones, Chelsea R; Nguyen, Betty T; Hashemian, Mohammad H; Malek, Melody; Gratton, Enrico; Nowick, James S.

doi:10.1039/d2sc01388f

Cited by 6 publications

(9 citation statements)

References 27 publications

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“…Of cells, 500 μl were centrifuged at 3,000 g for 5 min. The supernatant was discarded, and the cells were resuspended in 200 μl solution from a 1 μg ml −1 stock of the fluorescent analogue 26 Lys(Bodipy FL) 10 -teixobactin. The cells were allowed to incubate for the desired timepoints (1 min, 15 min and 45 min) at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

“…f , Static 31 P ssNMR spectra show membrane perturbation induced by teixobactin (cyan line) in contrast to the untreated lipid II-doped DOPC large unilamellar vesicles (black dashed line). g , Confocal microscopy with B. megaterium incubated in the presence of a fluorescent teixobactin analogue 26 . Intense, elongated teixobactin clusters form fast and get more compact after 45 min.…”

Section: Mainmentioning

confidence: 99%

“…To examine whether teixobactin oligomerization also occurs in bacteria, we visualized Bacillus megaterium cells with a fluorescent teixobactin analogue 26 using confocal microscopy (Fig. 1g,h ).…”

Section: Oligomerization and Membrane Damagementioning

confidence: 99%

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Teixobactin kills bacteria by a two-pronged attack on the cell envelope

Shukla

Lavore

Maity

et al. 2022

Nature

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106

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Antibiotics that use novel mechanisms are needed to combat antimicrobial resistance1–3. Teixobactin4 represents a new class of antibiotics with a unique chemical scaffold and lack of detectable resistance. Teixobactin targets lipid II, a precursor of peptidoglycan5. Here we unravel the mechanism of teixobactin at the atomic level using a combination of solid-state NMR, microscopy, in vivo assays and molecular dynamics simulations. The unique enduracididine C-terminal headgroup of teixobactin specifically binds to the pyrophosphate-sugar moiety of lipid II, whereas the N terminus coordinates the pyrophosphate of another lipid II molecule. This configuration favours the formation of a β-sheet of teixobactins bound to the target, creating a supramolecular fibrillar structure. Specific binding to the conserved pyrophosphate-sugar moiety accounts for the lack of resistance to teixobactin4. The supramolecular structure compromises membrane integrity. Atomic force microscopy and molecular dynamics simulations show that the supramolecular structure displaces phospholipids, thinning the membrane. The long hydrophobic tails of lipid II concentrated within the supramolecular structure apparently contribute to membrane disruption. Teixobactin hijacks lipid II to help destroy the membrane. Known membrane-acting antibiotics also damage human cells, producing undesirable side effects. Teixobactin damages only membranes that contain lipid II, which is absent in eukaryotes, elegantly resolving the toxicity problem. The two-pronged action against cell wall synthesis and cytoplasmic membrane produces a highly effective compound targeting the bacterial cell envelope. Structural knowledge of the mechanism of teixobactin will enable the rational design of improved drug candidates.

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Section: Methodsmentioning

confidence: 99%

Section: Mainmentioning

confidence: 99%

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Teixobactin kills bacteria by a two-pronged attack on the cell envelope

Shukla

Lavore

Maity

et al. 2022

Nature

Self Cite

106

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“…155 Recent studies have suggested that the bactericidal nature of teixobactin comes not only just from the sequestration of lipid II and thus from inhibiting the biosynthesis of peptidoglycan, but also from the resulting teixobactin fibril that displaces phospholipids, compromising the membrane integrity. 153,156,157 Since the discovery of teixobactin, the structurally similar hypeptin and clovibactin have also been characterized (Fig. 11).…”

Section: Teixobactinmentioning

confidence: 99%

Targeting membrane-bound bacterial cell wall precursors: a tried and true antibiotic strategy in nature and the clinic

et al. 2023

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“…This has resulted in the synthesis of various teixobactin analogues with enhanced and distinct modes of action, such as supramolecular assembly, which ultimately disrupts the cell membrane. [ 14 ].…”

Section: Revisiting Natural Products As a Source Of Novel Antibioticsmentioning

confidence: 99%

Emerging Non-Traditional Approaches to Combat Antibiotic Resistance

et al. 2022

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An increasing number of bacterial pathogens are acquiring resistance to the commonly used antibiotics. This has spurred a global threat leading to a resistance era and has penetrated the consciousness of the common people and the clinicians alike. The delay in discovering new antibiotics has exacerbated the resistance problem, forcing researchers to focus on unconventional antimicrobial therapeutics that differ from conventional antibiotics. Alternative therapies have emerged in recent years, including antimicrobial peptides, phage therapy, efflux pump inhibitors, antibodies, and immunomodulatory agents, which have produced impressive results in both laboratory and in clinical trials. Additionally, ultra-narrow-spectrum therapeutics such as CRISPR-Cas system and peptide nucleic acids aided in the development of sequence-specific antimicrobials. Moreover, combinatorial therapies that combine these new approaches have been efficient enough to get approval for clinical use and have accelerated the discovery of novel combination approaches that enhance the performance of already in-use antibiotics. In this review, we provide an overview of these approaches along with studies that focus on the uncharted microbial territories that have been able to deliver some of the important new antibiotics of recent times. It is hoped that the information gathered in this article will provide an update on the current antibiotic resistance threat and encourage profound research.

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Visualizing the mode of action and supramolecular assembly of teixobactin analogues in Bacillus subtilis

Abstract: Teixobactin has been the source of intensive study and interest as a promising antibiotic, because of its excellent activity against drug-resistant Gram-positive pathogens and its novel but not yet fully...

Cited by 6 publications

References 27 publications

Teixobactin kills bacteria by a two-pronged attack on the cell envelope

Teixobactin kills bacteria by a two-pronged attack on the cell envelope

Targeting membrane-bound bacterial cell wall precursors: a tried and true antibiotic strategy in nature and the clinic

Emerging Non-Traditional Approaches to Combat Antibiotic Resistance

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