Investigating the importance of charged residues in lantibiotics

Suda, Srinivas; Hill, Colin; Cotter, Paul D.; Ross, R. Paul

doi:10.4161/bbug.1.5.12353

Cited by 6 publications

(8 citation statements)

References 48 publications

(54 reference statements)

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“…This finding is of particular practical significance for further optimization of cyclic lipopeptide 3 and related peptides, considering that the net charge, and the number of positively charged residues, has been strongly correlated with biological activity for antimicrobial peptides. [52, 53] Predictably, control linear peptide 4 did not show activity against any of the ESKAPE bacteria, Table 1, supporting our previous study that indicated the importance of the cyclic structure for antibacterial activity. [34]…”

Section: Resultssupporting

confidence: 75%

Identification of novel cyclic lipopeptides from a positional scanning combinatorial library with enhanced antibacterial and antibiofilm activities

Bionda

Fleeman

Fuente-Núñez

et al. 2016

European Journal of Medicinal Chemistry

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Treating bacterial infections can be difficult due to innate or acquired resistance mechanisms, and the formation of biofilms. Cyclic lipopeptides derived from fusaricidin/LI-F natural products represent particularly attractive candidates for the development of new antibacterial and antibiofilm agents, with the potential to meet the challenge of bacterial resistance to antibiotics. A positional-scanning combinatorial approach was used to identify the amino acid residues responsible for driving antibacterial activity, and increase the potency of these cyclic lipopeptides. Screening against the antibiotic resistant ESKAPE pathogens revealed the importance of hydrophobic as well as positively charged amino acid residues for activity of this class of peptides. The improvement in potency was especially evident against bacterial biofilms, since the lead cyclic lipopeptide showed promising in vitro and in vivo anti-biofilm activity at the concentration far below its respective MICs. Importantly, structural changes resulting in a more hydrophobic and positively charged analog did not lead to an increase in toxicity toward human cells.

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Section: Resultssupporting

confidence: 75%

Identification of novel cyclic lipopeptides from a positional scanning combinatorial library with enhanced antibacterial and antibiofilm activities

Bionda

Fleeman

Fuente-Núñez

et al. 2016

European Journal of Medicinal Chemistry

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“…Examination of the extended collection of caseicin variants also indicates the absence of specific motifs within the peptides which are of great importance with respect to antimicrobial activity. This contrasts with the outcomes observed when similar strategies were employed to identify important domains in other antimicrobial peptides, such as the bacterially produced bacteriocins (26). In these other cases, key residues were identified on the basis of their complete intolerance to change.…”

Section: Discussioncontrasting

confidence: 41%

Extensive Manipulation of Caseicins A and B Highlights the Tolerance of These Antimicrobial Peptides to Change

Norberg

O’Connor

Stanton

et al. 2012

Appl Environ Microbiol

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Caseicins A and B are low-molecular-weight antimicrobial peptides which are released by proteolytic digestion of sodium caseinate. Caseicin A (IKHQGLPQE) is a nine-amino-acid cationic peptide, and caseicin B (VLNENLLR) is a neutral eight-aminoacid peptide; both have previously been shown to exhibit antibacterial activity against a number of pathogens, including Cronobacter sakazakii. Previously, four variants of each caseicin which differed subtly from their natural counterparts were generated by peptide synthesis. Antimicrobial activity assays revealed that the importance of a number of the residues within the peptides was dependent on the strain being targeted. In this study, this engineering-based approach was expanded through the creation of a larger collection of 26 peptides which are altered in a variety of ways. The investigation highlights the generally greater tolerance of caseicin B to change, the fact that changes have a more detrimental impact on anti-Gram-negative activity, and the surprising number of variants which exhibit enhanced activity against Staphylococcus aureus.

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“…The combined efforts of Lucy and Srinivas resulted in the generation of 16 additional derivatives and allowed us to confirm the importance of LtnαE24, reveal the requirement for positively charged residues in Ltnβ when targeting cells with reduced levels of cell envelope-associated D-alanylation or lysinylation and resulted in, for the first time, the creation of a derivative of a lacticin 3147 peptide (LtnβR27A) which displays enhanced specific activity, albeit only against Lactococcus lactis . Notably, however, this enhancement was not evident when this peptide was combined with its partner, Ltnα, peptide 31 , 32 . Prior to the completion of his studies, Srinivas also investigated the tolerance of the lanthionine structures in the two peptides to change.…”

Section: Standing On the Shoulder Of Giantsmentioning

confidence: 99%

“…Comprehensive bioengineering based strategies corresponding to those described above have also been employed to study and/or enhance other lantibiotics such as actagardine, mersacidin and nukacin ISK-1 47 - 50 . A number of other strategies have been successfully employed to facilitate the expression of lantibiotic gene clusters in quite different hosts, such as the expression of a S. pneumoniae encoded cluster in L. lactis 51 or of the B. licheniformis associated lichenicidin in Escherichia coli 32 . The other option available to bioengineers of bacteriocins is to utilize bacteriocin-associated modification proteins in vitro which provides even greater flexibility in terms of the changes that can be made.…”

Section: Legislationmentioning

confidence: 99%

“…Notably, however, this enhancement was not evident when this peptide was combined with its partner, Ltnα, peptide. 31 , 32 Prior to the completion of his studies, Srinivas also investigated the tolerance of the lanthionine structures in the two peptides to change. He noted that switching lanthionine and β-methyllanthionine bridges in the peptides had variable consequences.…”

Section: Standing On the Shoulder Of Giantsmentioning

confidence: 99%

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Bioengineering

Cotter

2012

Bioengineered

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While the bacteriocin Nisin has been employed by the food industry for 60 y, it remains the only bacteriocin to be extensively employed as a food preservative. This is despite the fact that the activity of Nisin against several food spoilage and pathogenic bacteria is poor and the availability of many other bacteriocins with significant potential in this regard. An alternative route to address the deficiencies of Nisin is the application of bioengineered derivatives of the peptide which, despite differing only subtly, possess enhanced capabilities of commercial value. The career path which has taken me from learning for the first time what bacteriocins are to understanding the potential of bacteriocin bioengineering has been a hugely enjoyable experience and promises to get even more interesting in the years to come.

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Investigating the importance of charged residues in lantibiotics

Cited by 6 publications

References 48 publications

Identification of novel cyclic lipopeptides from a positional scanning combinatorial library with enhanced antibacterial and antibiofilm activities

Identification of novel cyclic lipopeptides from a positional scanning combinatorial library with enhanced antibacterial and antibiofilm activities

Extensive Manipulation of Caseicins A and B Highlights the Tolerance of These Antimicrobial Peptides to Change

Bioengineering

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