Bypassing lantibiotic resistance by an effective nisin derivative

Zaschke-Kriesche, Julia; Behrmann, Lara V; Reiners, Jens; Lagedroste, Marcel; Gröner, Yvonne; Kalscheuer, Rainer; Smits, Sander H. J.

doi:10.1016/j.bmc.2019.06.031

Cited by 11 publications

(14 citation statements)

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“…The resistance protein SaNSR also recognizes the C-terminus of nisin (Khosa et al, 2016a), and cleaves nisin between the positions 28 and 29. Other studies showed that mutations in this area of the nisin molecule, e.g., S 29 P or C 28 P strongly reduce the efficiency of SaNSR (Field et al, 2019;Zaschke-Kriesche et al, 2019a). We assume that the exchange of His 31 against lysine in nisin H and the nisin H F 1 I variant (Figure 1) has the same effect on SaNSR thereby lowering the resistance efficiency to an IC 50 value of 52.4 ± 2.6 nM for nisin H and 44.2 ± 1.3 nM for the nisin H F 1 I variant, respectively (Figure 4 and Table 2).…”

Section: Discussionmentioning

confidence: 95%

Insights in the Antimicrobial Potential of the Natural Nisin Variant Nisin H

et al. 2020

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Lantibiotics are a growing class of antimicrobial peptides, which possess antimicrobial activity against mainly Gram-positive bacteria including the highly resistant strains such as methicillin-resistant Staphylococcus aureus or vancomycin-resistant enterococci. In the last decades numerous lantibiotics were discovered in natural habitats or designed with bioengineering tools. In this study, we present an insight in the antimicrobial potential of the natural occurring lantibiotic nisin H from Streptococcus hyointestinalis as well as the variant nisin H F 1 I. We determined the yield of the heterologously expressed peptide and quantified the cleavage efficiency employing the nisin protease NisP. Furthermore, we analyzed the effect on the modification via mass spectrometry analysis. With standardized growth inhibition assays we benchmarked the activity of pure nisin H and the variant nisin H F 1 I, and their influence on the activity of the nisin immunity proteins NisI and NisFEG from Lactococcus lactis and the nisin resistance proteins SaNSR and SaNsrFP from Streptococcus agalactiae COH1. We further checked the antibacterial activity against clinical isolates of Staphylococcus aureus, Enterococcus faecium and Enterococcus faecalis via microdilution method. In summary, nisin H and the nisin H F 1 I variant possessed better antimicrobial potency than the natural nisin A.

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Section: Discussionmentioning

confidence: 95%

Insights in the Antimicrobial Potential of the Natural Nisin Variant Nisin H

et al. 2020

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“…Interestingly, ripcin B-G, which are hybrid peptides of two inactive (against Gram-negative pathogens) peptides, i.e., nisin(1-20) and ripcin, showed substantial antimicrobial activity against the tested Gram-negative pathogens. Moreover, ripcin B-G were fully resistant against the NSR, while efficient degradation takes place with full nisin 44,45 , making our hybrid peptides more attractive for application in complex microbial environments like the gut or skin, also in view of their higher target specificity. Mode of action studies show that (which was not certified by peer review) is the author/funder.…”

Section: Discussionmentioning

confidence: 99%

“…To investigate the stability of ripcin B-G against the nisin resistance protein (NSR) 44,45 , a peptidase that cleaves the C-terminus last 6 amino acids of nisin, a MIC test was performed by using NSR producing strain L. lactis NZ9000 (pNZ-SV-SaNSR, Em r ) 45 and non-NSR producing strain L. lactis NZ9000 (pNZ8048-Em r , Em r ) 46 . Due to cleave of the C-terminus last 6 amino acids of nisin by NSR protease, the antimicrobial activity of nisin against L. lactis NZ9000 decreased 100-fold in the presence of the NSR protease (Table 2).…”

Section: Ripcin B-g Show Selective Antimicrobial Activity Against S Aureusmentioning

confidence: 99%

“…For the nisin resistance protein-producing strain L. lactis NZ9000 (pNZ-SV-SaNSR, Em r ) 45 and non-NSR-producing strain L. lactis NZ9000 (pNZ8048-Em r , Em r ) 46 , the MIC tests were performed in GM17, supplemented with erythromycin (5 μg/ml) and nisin (1ng/mL, for maintenance of the induction of NSR). L. lactis NZ9000 strains were induced by nisin at a concentration of 5 ng/mL for 3 h before exposing them to antibiotics.…”

Section: Lc-ms/ms Analysismentioning

confidence: 99%

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Nisin- and ripcin-derived hybrid lanthipeptides display selective antimicrobial activity against Staphylococcus aureus

Zhao

Kuipers

2021

Preprint

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Lanthipeptides are (methyl)lanthionine ring-containing ribosomally synthesized and post-translationally modified peptides (RiPPs). Many lanthipeptides show strong antimicrobial activity against bacterial pathogens, including antibiotic-resistant bacterial pathogens. The group of disulfide bond-containing antimicrobial peptides (AMPs) is well known in nature and forms a rich source of templates for the production of novel peptides with corresponding (methyl)lanthionine analogues instead of disulfides. Here, we show that novel macrocyclic lanthipeptides (termed thanacin and ripcin) can be synthesized using the known antimicrobials thanatin and rip-thanatin as templates. Notably, the synthesized nisin(1-20)-ripcin hybrid lanthipeptides (ripcin B-G) showed selective antimicrobial activity against S. aureus, including an antibiotic-resistant MRSA strain. Interestingly, ripcin B-G, which are hybrid peptides of nisin(1-20) and ripcin, respectively, that are each inactive against Gram-negative pathogens, showed substantial antimicrobial activity against the tested Gram-negative pathogens. Moreover, ripcin B-G was highly resistant against the nisin resistance protein (NSR; a protease could cleave nisin and strongly reduce its activity ), opposed to nisin itself. Mode of action studies show that ripcin C exerts its antimicrobial activity against Gram-positive pathogens by binding to the cell wall synthesis precursor lipid II and thereafter arrests cell growth. In addition, ripcin C exerts its antimicrobial activity against Gram-negative pathogens by binding to LPS and the cell wall synthesis precursor lipid II. This study provides an example of converting disulfide bond-based AMPs into (methyl)lanthionine-based macrocyclic hybrid lanthipeptides and can yield antimicrobial peptides with selective antimicrobial activity against S. aureus.

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“…It is expressed by the nsr operon with other lantibiotic resistance genes, such as nsrFP and nsrRK (Khosa et al, 2013(Khosa et al, , 2015(Khosa et al, , 2016. However, modified nisin molecules were able to maintain activity against strains possessing SaNSR (Hayes et al, 2019;Zaschke-Kriesche et al, 2019). Another mode of escaping the degrading activity of AMPs is via inhibitory molecules capable of binding to the nisin site of SaNSR (Porta et al, 2019).…”

Section: Proteases and Other Proteinsmentioning

confidence: 99%

Resistance Mechanisms to Antimicrobial Peptides in Gram-Positive Bacteria

et al. 2020

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With the alarming increase of infections caused by pathogenic multidrug-resistant bacteria over the last decades, antimicrobial peptides (AMPs) have been investigated as a potential treatment for those infections, directly through their lytic effect or indirectly, due to their ability to modulate the immune system. There are still concerns regarding the use of such molecules in the treatment of infections, such as cell toxicity and host factors that lead to peptide inhibition. To overcome these limitations, different approaches like peptide modification to reduce toxicity and peptide combinations to improve therapeutic efficacy are being tested. Human defense peptides consist of an important part of the innate immune system, against a myriad of potential aggressors, which have in turn developed different ways to overcome the AMPs microbicidal activities. Since the antimicrobial activity of AMPs vary between Gram-positive and Gram-negative species, so do the bacterial resistance arsenal. This review discusses the mechanisms exploited by Gram-positive bacteria to circumvent killing by antimicrobial peptides. Specifically, the most clinically relevant genera, Streptococcus spp., Staphylococcus spp., Enterococcus spp. and Gram-positive bacilli, have been explored.

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Bypassing lantibiotic resistance by an effective nisin derivative

Cited by 11 publications

References 68 publications

Insights in the Antimicrobial Potential of the Natural Nisin Variant Nisin H

Insights in the Antimicrobial Potential of the Natural Nisin Variant Nisin H

Nisin- and ripcin-derived hybrid lanthipeptides display selective antimicrobial activity against Staphylococcus aureus

Resistance Mechanisms to Antimicrobial Peptides in Gram-Positive Bacteria

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