AMPs & AMR

AMPLY

HIGH-THROUGHPUT NOVEL ANTIMICROBIAL DISCOVERY FROM 'OMIC DATASOURCES


info@amply.systems

FINDING AMPs


To date, AMPLY has identified over 400 entirely novel, bioactive, antimicrobial peptides across datasets as diverse as Peruvian poison dart frogs, the ruminal eukaryotome, human upper bronchial tract and various plant species. Leveraging the direct connection between next generation sequencing, high-throughput, tailored prospect selection and large scale synthesis technologies, AMPLY can deliver high volumes of medically viable, naturally sourced compounds for a fraction of the cost of alternative methods. 


AMPLY was designed originally as part of a Life Science Network Wales PhD project by (mature student) Ben Thomas. Using techniques from the predictive marketing, financial modelling and telecommunications industries he created a software pipeline using a mix of "big data" processing techniques, offering a new approach to high-throughput annotation and elucidation of biological datasets. The key to AMPLY's success is the relationship between the in silico prediction and the feedback loop from in vitro testing. Models in AMPLY are improved and refined as each new batch of compounds is tested, improving their detection and retrieval rate for future analysis runs.


While AMPLY is not available as downloadable software, the entire processing chain is presented as a service platform. Sequenced biological data is ubiquitous and cheap to obtain, however the analysis and publication of this data is more difficult without an aspect of novelness or wider scientific interest. AMPLY is an efficient way to take data that might be unused and leverage it for possible publishable or patentable resuts for the fraction of the costs of a large scale drug discovery platform.  The picture above (provided by Jurnorain Gani, from the St. George's University Hospital imaging facility) demonstrates an AMP disrupting the membrane of an MDR strain of E. coli. This low-toxicity, highly efficient, entirely novel antibiotic was retrived by AMPLY analysing a single plant genome. End to end this can be done for a cost measured in hundreds, not thousands of pounds. 


FIGHTING AMR



AMR 

The rise of antibiotic resistant strains of microbes (bacteria, parasites, viruses and fungi) is probably the leading threat facing the ongoing survival and maintenance of human civilization in its current form. It is neither hysterical nor fearmongering talk to consider an upcoming era where treatments such as chemotherapy and simple surgery will become impossible due to their reliance on functioning antibiotics. We are, perhaps, already 20 years behind in this microbial arms-race having strip-mined to exhaustion naturally occurring antibiotics and with little financial incentive to hunt further afield (as pharmaceutical companies ignore the issue and instead target chronic illnesses to maximise potential profits) [1].


The real implications of AMR will be global, with developing and emerging nations bearing the brunt of the fallout. Routine surgeries and minor infections will become life-threatening and progress made in the reduction of the impact of infectious diseases made in the last fifty years will be jeopardised. These are not abstract or future problems. At the time of writing, in 2018, papers are still being released with warnings about the future impact of AMR, but drug resistant infections already claim 50,000 lives each year in Europe and the US alone [2]. Globally, today, at least 700,000 die each year of AMR related illnesses [3], [4]. This is not an abstract future issue: many have evocatively termed what is occurring right now a microbial holocaust [5] and a medical Dark Age is approaching unless pro-active and timely action is taken to prevent the situation worsening.


AMPs as a theraputic tool

The first eukaryotic AMP to be discovered was isolated from rabbit leukocytes in 1956 [6], [7]. There are distinct differences in the antimicrobial activities of eukaryotic and prokaryotic AMPs. AMPs from eukaryotic cells show wide-ranging activity against gram-negative and gram-positive bacteria; AMPs from prokaryotic organisms often feature relatively narrow inhibitory spectra, with many being active against only species and genera related to the AMP-producing bacteria themselves [8]. Prokaryotic AMPs often exhibit much higher antimicrobial potency than eukaryotic AMPs, killing at nanomolar rather than micromolar concentrations [9].


Eukaryotic AMPs are evolutionarily ancient weapons and their ubiquity throughout the animal and plant kingdoms supports the hypothesis that they have played a key role in the successful evolution of complex multicellular organisms [165]. Despite their ancient lineage, antimicrobial peptides have remained effective, bringing into question the inevitability of the fact that bacteria, fungi and viruses have the potential to develop resistance to harmful substances [12]. Eukaryotic AMPs commonly operate with low antigenicity, are relatively small (<10 kDa), cationic, amphipathic and highly variable in length, sequence and structure [11], [8]. A significant diversity of eukaryotic AMPs has been isolated from a wide variety of animals (vertebrates and invertebrates), plants, archaea and fungi.


AMPLY's hunt is for short (8-50aas), monomeric, non-toxic, therapeutically viable, gene-encoded, non-post-translationally modified peptides. These peptides have a number of therapeutic benefits: they can kill remarkably quickly (in under 30 minutes), can be either highly specific, or generalised killers, have efficient anti-biofilm action and are difficult for pathogens to aquire resistance to and are short enough to be synthesised from scratch. Short to medium term therapeutic targets for AMPs are topical antifungals and antibiotics, with the longer term aim to look at animal and human treatments for oral ingestion. 



[1]         R. I. Aminov, “A brief history of the antibiotic era: Lessons learned and challenges for the future,” Front. Microbiol., vol. 1, no. DEC, p. 134, Dec. 2010.

[2]         World Health Organization Regional Office for Europe, “WHO | Measles and Rubella Surveillance Data,” WHO, 2018.

[3]         X. Yin, J. Zhang, and X. Wang, “Sequential injection analysis system for the determination of arsenic by hydride generation atomic absorption spectrometry,” Fenxi Huaxue, vol. 32, no. 10, pp. 1365–1367, 2004.

[4]         Review on Antimicrobial Resistance and J. O’Neill, “Antimicrobial Resistance : Tackling a crisis for the health and wealth of nations,” Rev. Antimicrob. Resist., no. December, pp. 1–16, 2014.

[5]         I. D. Khan et al., “PANRESISTANT SUPERBUGS: ARE WE AT THE EDGE OF A ‘MICROBIAL HOLOCAUST,’” Int. J. Med. Med. Res., vol. 0, no. 2, Dec. 2017.

[6]      N. Antcheva, F. Guida, and A. Tossi, “Defensins,” in Handbook of Biologically Active Peptides, 2013, pp. 101–118.

[7]     R. I. Lehrer, “Primate defensins,” Nature Reviews Microbiology, vol. 2, no. 9. Nature Publishing Group, pp. 727–738, 01-Sep-2004.

[8]     A. J. Park, J. P. Okhovat, and J. Kim, “Antimicrobial peptides,” in Clinical and Basic Immunodermatology: Second Edition, vol. 26, no. 1, Cell Press, 2017, pp. 81–95.

[9]     S. Maher and S. McClean, “Investigation of the cytotoxicity of eukaryotic and prokaryotic antimicrobial peptides in intestinal epithelial cells in vitro,” Biochem. Pharmacol., vol. 71, no. 9, pp. 1289–1298, Apr. 2006.

[10]     Z. M., “Antimicrobial peptides of multicellular organisms. [Nature. 2002] - PubMed - NCBI,” Nature., vol. 415, pp. 389–395, 2013.

[11]     A. J. Park, J. P. Okhovat, and J. Kim, “Antimicrobial peptides,” in Clinical and Basic Immunodermatology: Second Edition, vol. 6, no. 12, Multidisciplinary Digital Publishing Institute, 2017, pp. 81–95.

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