Dissecting the Binding Interactions of Teixobactin with the Bacterial Cell‐Wall Precursor Lipid II

Chiorean, Sorina; Antwi, Isaac; Carney, Daniel W.; Kotsogianni, Ioli; Giltrap, Andrew M.; Alexander, Francesca M.; Cochrane, Stephen A.; Payne, Richard J.; Martin, Nathaniel I.; Henninot, Antoine; Vederas, John C.

doi:10.1002/cbic.201900504

Cited by 25 publications

(22 citation statements)

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“…Alternatively, it has been proposed that AMPs cause microbial death via interaction with intracellular targets by inhibiting cell wall, DNA, RNA, and/or protein synthesis [37][38][39]. Examples of AMPs with intracellular targets include teixobactin that prevents cell wall synthesis by binding the peptidoglycan precursor lipid II [40], indolicidin that binds to DNA thereby inhibiting DNA replication [41], the larvae peptide Lser-PRP2 that is suggested to inhibit protein folding by binding to the bacterial chaperone DnaK [42], and the proline-rich peptide Bac5 that blocks translation by binding to ribosomes [43].…”

Section: Introductionmentioning

confidence: 99%

Rondonin: antimicrobial properties and mechanism of action

et al. 2021

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Infectious diseases are among the major causes of death in the human population. A wide variety of organisms produce antimicrobial peptides (AMPs) as part of their first line of defense. A peptide from Acanthoscurria rondoniae plasma, rondonin -with antifungal activity, a molecular mass of 1,236 Da and primary sequence IIIQYEGHKH -was previously studied (Uniprot accession number B3EWP8). It showed identity with the C-terminus of subunit "D" of the hemocyanin of the Aphonopelma hentzi spider. This result led us to propose a new pathway of the immune system of arachnids that suggests a new function to hemocyanin: production of antimicrobial peptides.Rondonin does not interact with model membranes and was able to bind to yeast nucleic acids but not bacteria. It was not cytotoxic against mammalian cells. The antifungal activity of rondonin is pH dependent and peaks at pH ~4-5. The peptide presents synergism with Gomesin (spider hemocyte antimicrobial peptide -UniProtKB -P82358) against human yeast pathogens, suggesting a new potential alternative treatment option. Antiviral activity was detected against RNA viruses, measles, H1N1 and encephalomyocarditis. This is the first report of an arthropod hemocyanin fragment with activity against human viruses. Currently, it is vital to invest in the search for natural and synthetic antimicrobial compounds that, above all, present alternative mechanisms of action to first-choice antimicrobials.

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Section: Introductionmentioning

confidence: 99%

Rondonin: antimicrobial properties and mechanism of action

et al. 2021

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“…Recently, a collaborative effort between the Cochrane, Payne, Martin and Vederas groups, and the Ferring Research Institute, showed that H-TriA 1 significantly improves the antimicrobial activity of teixobactin analogues to include Gram-negative strains. 34 Perhaps the most significant observation was a 125-fold decrease in MIC of native teixobactin against Salmonella enterica when co-administered with H-TriA 1 at 12.5 μg mL −1 .…”

Section: Resurgence Of the Tridecaptins: Establishing A Structure–activity Relationshipmentioning

confidence: 99%

The tridecaptins: non-ribosomal peptides that selectively target Gram-negative bacteria

2021

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“…In addition, brevibacillin 2V also showed binding to membrane-embedded Lipid II, albeit with somewhat lower affinity with a Kd value of 7.9 μm (Figure 5B). Nisin, teixobactin, nukacin ISK-1, and lacticin 3147 are wellknown Lipid II-binding antibiotics; among these antibiotics, nisin showed the strongest binding affinity to membraneembedded Lipid II with a Kd value of 14.6 nm, and lacticin 3147 showed the lowest binding affinity to membrane-embedded Lipid II with a Kd value of 0.92 μm (Islam et al, 2012;'t Hart et al, 2016;Bakhtiary et al, 2017;Chiorean et al, 2020). In this study, brevibacillins showed solid-binding affinities (Kd, 0.9 μm to 7.9 μm), and they were reported to have comparable antimicrobial activities as nisin and lacticin 3147 against the tested bacterial pathogens .…”

Section: Brevibacillin and Brevibacillin 2v Show Good Affinity To Lipid IImentioning

confidence: 99%

Brevibacillin 2V Exerts Its Bactericidal Activity via Binding to Lipid II and Permeabilizing Cellular Membranes

et al. 2021

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Lipo-tridecapeptides, a class of bacterial non-ribosomally produced peptides, show strong antimicrobial activity against Gram-positive pathogens, including antibiotic-resistant Staphylococcus aureus and Enterococcus spp. However, many of these lipo-tridecapeptides have shown high hemolytic activity and cytotoxicity, which has limited their potential to be developed into antibiotics. Recently, we reported a novel antimicrobial lipo-tridecapeptide, brevibacillin 2V, which showed no hemolytic activity against human red blood cells at a high concentration of 128 mg/L, opposite to other brevibacillins and lipo-tridecapeptides. In addition, brevibacillin 2V showed much lower cytotoxicity than the other members of the brevibacillin family. In this study, we set out to elucidate the antimicrobial mode of action of brevibacillin 2V. The results show that brevibacillin 2V acts as bactericidal antimicrobial agent against S. aureus (MRSA). Further studies show that brevibacillin 2V exerts its bactericidal activity by binding to the bacterial cell wall synthesis precursor Lipid II and permeabilizing the bacterial membrane. Combined solid-state NMR, circular dichroism, and isothermal titration calorimetry assays indicate that brevibacillin 2V binds to the GlcNAc-MurNAc moiety and/or the pentapeptide of Lipid II. This study provides an insight into the antimicrobial mode of action of brevibacillin 2V. As brevibacillin 2V is a novel and promising antibiotic candidate with low hemolytic activity and cytotoxicity, the here-elucidated mode of action will help further studies to develop it as an alternative antimicrobial agent.

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Dissecting the Binding Interactions of Teixobactin with the Bacterial Cell‐Wall Precursor Lipid II

Cited by 25 publications

References 22 publications

Rondonin: antimicrobial properties and mechanism of action

Rondonin: antimicrobial properties and mechanism of action

The tridecaptins: non-ribosomal peptides that selectively target Gram-negative bacteria

Brevibacillin 2V Exerts Its Bactericidal Activity via Binding to Lipid II and Permeabilizing Cellular Membranes

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