Arenicins are a group of
antimicrobial peptides
Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for a ...
being studied to combat
Gram-negative bacteria.
The arenicin family consists of three different peptides: arenicin-1, arenicin-2, and the most recently discovered, arencin-3.
[Neve, S., Raventós, D., et al]
"NZ17074 : An Arenicin-3 variant found by HTS screening of yeast libraries"
. Novozymes A/S. Copenhagen: Adenium Biotech, Web. 21 Nov. 2012.
Given the growing acquisition of
multidrug resistance
Multiple drug resistance (MDR), multidrug resistance or multiresistance is antimicrobial resistance shown by a species of microorganism to at least one antimicrobial drug in three or more antimicrobial categories. Antimicrobial categories are c ...
among bacterial
pathogens, particularly in Gram-negative bacteria, the development of arenicin as a novel drug treatment has been under way. Arenicin-3 has been of particular interest in the fight against urinary tract infections caused by ''
E. coli
''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
'' strains. It is also being developed with the intention of treating hospital acquired infections. In both applications, there are two proposed modes of action by which arenicin-3 interacts with the bacteria.
[Adenium Biotech Aps. EP2509617A1, 2012]
"Arenicin-3 for use in the treatment of urinary tract infections"
/ref>
Adenium Biotech currently remains in the preclinical
In drug development, preclinical development, also termed preclinical studies or nonclinical studies, is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and drug ...
testing period of their product, arenicin-3. Toxicology
Toxicology is a scientific discipline, overlapping with biology, chemistry, pharmacology, and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnosing and treating expo ...
, drug efficacy, and other information have yet to be determined with further research completed in clinical settings. However, with Gram-negative bacteria causing 65% of hospital-acquired infections, the commercial market for arenicin is large.
Background (discovery and development)
The drug arenicin was discovered by the company Adenium Biotech, which spun off from Novozymes
Novozymes A/S is a global biotechnology company headquartered in Bagsværd outside of Copenhagen, Denmark. The company's focus is the research, development and production of industrial enzymes, microorganisms, and biopharmaceutical ingredients.
...
A/S in 2011 and was given funding support from NovoSeeds and Sunstone Life Science Ventures Fund III. The compound was initially found in secretions from the lugworm, and is part of its defense against invasive bacteria. Adenium Biotech currently holds patents for arenicin’s use against urinary tract infections.
Structure
Arenicin-1 is composed of 21 amino acids
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
with a beta hairpin
The beta hairpin (sometimes also called beta-ribbon or beta-beta unit) is a simple protein structural motif involving two beta strands that look like a hairpin. The motif consists of two strands that are adjacent in primary structure, oriented in ...
structure. It contains one disulfide bond connecting Cys3 and Cys20, which forms its unique 18 amino acid ring.
Arenicin-2 is a 21 amino acid peptide with a beta hairpin structure in aqueous solution. It has one disulfide bond and nine hydrogen bonds
In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...
, giving it a stable structure.
Arenicin-3 is a 21 amino acid peptide with the sequence GFCWYVCYRNGVRVCYRRCN. It has two disulfide bonds bridging between Cys2, Cys20 and Cys7, Cys16. In aqueous solution arenicin-3 takes on a beta hairpin structure. Due to the 4 positive arginines along with nine hydrophobic amino acids, arenicin-3 is amphipathic.
Mode of action
There are currently two proposed mode of action A mode of action (MoA) describes a functional or anatomical change, resulting from the exposure of a living organism to a substance. In comparison, a mechanism of action (MOA) describes such changes at the molecular level.
A mode of action is impor ...
s, but the exact mechanism is still under active research.
Cationic residues on arenicin-3 interacts with negatively charged lipopolysaccharides on the outer membrane of Gram-negative bacteria. Peptides that were translocated across the outer membrane create pores in the cytoplasmic membrane, thereby disrupting the osmotic balance of the cell. Studies showing the influx of TRITC and efflux of ATP
ATP may refer to:
Companies and organizations
* Association of Tennis Professionals, men's professional tennis governing body
* American Technical Publishers, employee-owned publishing company
* ', a Danish pension
* Armenia Tree Project, non ...
supports this hypothesis. In addition, arenicin-3 does not seem to induce cell lysis, which is important in the avoidance of sepsis during infection.[Nielsen.]
Peptides that were translocated into the cell membrane then exert a secondary effect by inhibiting protein synthesis. It is hypothesized this mode of action is similar to that of tachyplesin I, which binds to the minor groove of DNA.bactericidal
A bactericide or bacteriocide, sometimes abbreviated Bcidal, is a substance which kills bacteria. Bactericides are disinfectants, antiseptics, or antibiotics.
However, material surfaces can also have bactericidal properties based solely on their ...
properties of arenicin-3 are responsible for its efficacy in inducing a 3- log reduction of ''E. coli'' bacterial load within 4 hours in a murine
The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. Members of this subfamily are called murines. In terms of species richness, this subfamily is larger than all mammal families excep ...
peritonitis model. Further experiments showed no significant inoculum effect on arenicin-3 in an ''E. coli'' survival curve experiment, improving the potential for the compound to be developed into a useful therapeutic.[Sandvang, D., Markvardsen, et al]
“NZ17074 - A Novel antimicrobial peptide showing potent in vitro activity against gram negative multi-resistant clinical isolates”
. Novozymes A/S. Copenhagen: Adenium Biotech, Web. 20 Nov. 2012.
Uses
The arenicin family has shown to have bactericidal effects on a broad range of multi-drug resistant Gram-negative and Gram-positive bacteria in both in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
and in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
studies.
References
{{reflist
Antimicrobial peptides
Experimental drugs