The gene encoded antimicrobial peptides, a template for the design of novel anti-mycobacterial drugs

Carroll, James A.; Field, Des; O’Connor, Paula M.; Cotter, Paul D.; Coffey, Aidan; Hill, Colin; Ross, R. Paul; O’Mahony, Jim

doi:10.4161/bbug.1.6.13642

Cited by 53 publications

(25 citation statements)

References 21 publications

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“…A distinguishing component of this study is the identification of the genetic locus responsible for the biosynthesis of laterosporulin10. These findings will further help in identifying more natural variants, in the creation of recombinant variants of laterosporulin10 or in bioengineering of laterosporulin10 for improving its efficacy against Mtb, as was done earlier for Nisin A (Carroll et al, 2010a).…”

Section: Discussionmentioning

confidence: 76%

“…Thus, it fulfils the need for identification of species-specific bacteriocins, which is an important step in the direction of generating M. tuberculosis specific drugs. Earlier, NisinA was bio-engineered to create variants with species-specific activity against M. tuberculosis (Carroll et al, 2010a). Among other bacteriocins studied, lacticin 3147, produced by Lactococcus lactis subsp.…”

Section: Discussionmentioning

confidence: 99%

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Laterosporulin10: a novel defensin like Class IId bacteriocin from Brevibacillus sp. strain SKDU10 with inhibitory activity against microbial pathogens

et al. 2016

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Bacteriocins are antimicrobial peptides (AMPs) produced by bacteria to acquire survival benefits during competitive inter-and intra-species interactions in complex ecosystems. In this study, an AMP-producing soil bacterial strain designated SKDU10 was isolated and identified as a member of the genus Brevibacillus. The AMP produced by strain SKDU10 identified as a class IId bacteriocin with 57.6 % homology to laterosporulin, a defensin-like class IId bacteriocin. However, substantial differences were observed in the antimicrobial activity spectrum of this bacteriocin named laterosporulin10 when compared to laterosporulin. Laterosporulin10 effectively inhibited the growth of Staphylococcus aureus and Mycobacterium tuberculosis (Mtb H37Rv) with LD 50 values of 4.0 µM and 0.5 µM, respectively. Furthermore, laterosporulin10 inhibited the growth of Mtb H37Rv strain at about 20 times lower MIC value compared to S. aureus MTCC 1430 or M. smegmatis MC2 155 in vitro and ex vivo. Electron micrographs along with membrane permeabilization studies using FACS analysis revealed that laterosporulin10 is a membrane-permeabilizing peptide. Interestingly, laterosporulin10 was able to efficiently kill Mtb H37Rv strain residing inside the macrophages and did not show haemolysis up to 40 µM concentration.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Laterosporulin10: a novel defensin like Class IId bacteriocin from Brevibacillus sp. strain SKDU10 with inhibitory activity against microbial pathogens

et al. 2016

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“…As a result of developing this assay, we confirmed that all three nisin variants have enhanced activity against a number of representative pathogenic mycobacteria. 27 Interestingly, results from this assay indicated that these peptides have species and sub-species specificities. This characteristic may one day facilitate the targeting of specific pathogens whilst maintaining the natural bacterial flora.…”

Section: Conclusion and Future Prospectsmentioning

confidence: 97%

Anti-mycobacterial peptides: Made to order with delivery included

Carroll¹,

Mahony²

2011

Bioengineered Bugs

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"TB is too often a death sentence. It does not have to be this way,"- Nelson Mandela. Despite the success of anti-mycobacterial drugs over the past 70 years, mycobacterial disease, particularly tuberculosis is still responsible for millions of annual deaths worldwide. Additionally, the emergence of Multidrug Resistant (MDR-TB) and Extensively Drug Resistant (XDR-TB) Tuberculosis has motivated calls by the World Health Organization (WHO) for novel drugs, vaccines and diagnostic tests. Consequently, the identification and evaluation of a range of anti-mycobacterial compounds against pathogenic mycobacterial species is of paramount importance. My colleagues and I at Cork Institute of Technology (CIT) and University College Cork (UCC) have tackled this issue through the initial optimization of the rapid, robust and inexpensive microtitre alamarBlue assay (MABA) and subsequent employment of this assay to facilitate the rapid assessment of a new wave of potential therapeutic compounds, namely bacteriocins, in particular type 1 bacteriocins known as lantibiotics. The gene encoded nature of these peptides facilitates their genetic manipulation and consequent activities as anti-microbial agents. In this regard, it may be possible to one day develop diverse populations of anti-mycobacterial bacteriocins with species specific activities. This may in turn provide more targeted therapies, resulting in less side effects, shorter treatment times and thus better patient compliance. Although current drug regimes are effective in the interim, previous lessons have taught us not to be complacent. In the words of the Intel founder Andrew Grove, 'Success breeds complacency. Complacency breeds failure. Only the paranoid survive'. Armed with knowledge of previous failures, it is the duty of the scientific community to anticipate future bacterial resistance and have an arsenal of compounds standing by in such an eventuality.

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“…The producers of the most interesting Nisin derivatives were re-created using a "food-grade" approach corresponding to that described for lacticin 3147 above and further investigations with M21V and K22T, which were renamed Nisin V and Nisin T, respectively, established that both peptides exhibited enhanced activity relative to Nisin A against a broad spectrum of targets. More specifically, broth-based minimum inhibitory concentration assays revealed that Nisin T was enhanced against S. agalactiae , Streptococus mutans , Clostridium difficile , several S. aureus strains , L. lactis and a variety of mycobacteria while Nisin V was enhanced against this same selection but differed by virtue of also exhibiting enhanced activity against Listeria monocytogenes , Enterococcus faecium and Bacillus cereus 43 , 44 . These enhanced potencies were apparent when growth and kill curve type assays were employed or when Nisin V was added to frankfurter meat in order to control a lux -tagged L. monocytogenes 43 .…”

Section: Nisincrediblementioning

confidence: 99%

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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The gene encoded antimicrobial peptides, a template for the design of novel anti-mycobacterial drugs

Cited by 53 publications

References 21 publications

Laterosporulin10: a novel defensin like Class IId bacteriocin from Brevibacillus sp. strain SKDU10 with inhibitory activity against microbial pathogens

Laterosporulin10: a novel defensin like Class IId bacteriocin from Brevibacillus sp. strain SKDU10 with inhibitory activity against microbial pathogens

Anti-mycobacterial peptides: Made to order with delivery included

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