use of synthetic antimicrobial peptides to facilitate the
our laboratory identified molecules having the ability to boost the effectiveness of anti-infective agents.
these molecules have themselves anti-infective properties (antibacterial and antifungal) and are
able to increase the effectiveness of antibiotics already commercially available.
We study the effect of different synthetic peptides characterized in our laboratory. at micromolar
concentrations, these cationic linear peptides have lytic properties against gram-positive bacteria,
teChnology fungi and yeasts; whereas they are not lytic for the host cells and can stimulate neutrophils by inducing
entry of extracellular calcium. they are able to destabilize the membranes of microorganisms, thereby
allowing the entry of the antibiotic to reach its intracellular target.
Preliminary studies have shown the synergistic effect of these peptides with antibiotics.
for example one of the identified molecule acts at a concentration of 10 mM and has a synergistic
action at 4 microM with existing antibiotics. for instance, the voniconazol antibiotic acts at a
concentration of 0.5μg/ml. We cut to a dose of 0.125μg/ml by adding 4 mM of the peptides identified
at last but not least, besides the therapeutic aspect, the peptides of interest identified by the
laboratory can be used in a diagnostic frame (prognostic biomarkers) : the presence or not of the
natural molecule in the patient will allow the prediction whether the patient may respond to anti-
so far in vitro experiments using a combination of peptides of the collection comprising voriconazole,
linezolid, amoxicillin and metronidazole showed synergistic properties of the peptides decreasing
twice or three times the concentration of antibiotic. this also presents a double interest:
reduce the toxicity, very frequent with these drugs at very narrow therapeutic index in some patients
aDVantages (particularly the patients severely affected with liver and kidney dysfunctions consecutive to the
Moreover, this combination authorizes the action of antibiotics in question, even when the patient
does not have the proteins required for their action.
aPPliCations new treatment of bacterial or fungal infections
We contemplate the application for a patent on the invention and are willing to enter a collaborative
partnership with one or more industrials partners interested in the study aiming at identifying the
in close relation with chemists our laboratory has the ability to insert these peptides in coating materials for dental prostheses, catheters, surgical instruments or dressings.
the emergence of a large number of microorganisms resistant to conventional antibiotics is a major
public health problem. as long as gram-positive infections are concerned, several therapeutic options
are developed. the urgent need concerns drugs effective against pathogenic bacteria and fungi,
gram- . the stakes are high because the number of immunocompromised patients is increasing
due to the increased number of patients treated with immunosuppressive drugs (organ transplant
recipients of all, autoimmune diseases and systemic inflammatory .). the resistance of microorganisms to antibiotics is highly dependent on the integrity of the outer
membrane, this structure acts as a permeable barrier and effectively prevents many antimicrobial
baCKgrounD agents to reach their intracellular targets .
because the lPs plays a crucial role in the stability of the outer membrane and is present in many
pathogens, most of the implemented strategies consist in agents able to target it. these are the PaMs
which by their amphipathic and cationic nature are able to bind lPs, destabilize the outer membrane
and kill the target cell by mechanisms that are not yet fully understood [3-5]; thus it was reported that while some PaMs were added to a concentration below its MiC, they are
capable of altering the permeability of the outer membrane thus rendering the bacteria sensitive to
antibiotics that are inactive in the presence of an intact membrane [ 6, 7].
1-livermore, D. M. 2009. has the era of untreatable infections arrived? J. antimicrob. Chemother. 64 suppl 1:i29-36.
2-Delcour, a. h. 2009. outer membrane permeability and antibiotic resistance. biochim. biophys. acta. 1794:808-8163-Jenssen, h., P. hamil , and r. e. hancock. 2006. Peptide antimicrobial agents.Clin. Microbiol. rev. 19:491-51]4-brogden, K. a. 2005. antimicrobial peptides: pore f ormers or metabolic inhibitors in bacteria? nat. rev. Microbiol.
3:238-50.]5-lohner, K., and s. e. blondel e. 2005. Molecular mechanisms of membrane perturbation by antimicrobial peptides
and the use of biophysical studies in the design of novel peptide antibiotics. Comb. Chem. high throughput screen.
6-savage, P. b. 2001. Multidrug-resistant bacteria: overcoming antibiotic permeability barriers of gram-negative
bacteria. ann. Med. 33:167-171.
7-Vaara, M. 1992. agents that increase the permeability of the outer membrane. Microbiol. rev. 56:395-411.
8-lugardon, K. et al., 2001. structural and bniological characterization of chromofungin, the antifungal chromogranin
bibliograPhy a-(47-66)-derived peptide. J. biol. Chem. 276:35875-35882.
9-strub, J. M. et al., 1996, antibacterial activity of secretolytin, a chromogranin b-derived peptide (614-626) is correlated
with peptide structuee. frbs lett. 379:273-278.
10-briolat, J. et al., 2005, new antimicrobial activity for the catecholamine release-inhibitory peptide from chromogranin
a. Cel . Mol. life sci. 62:377-385.
11-strub, J. M. et al., 1996, antibacterial activity of glycosylated and phosphorylated chromogranin a-derived-peptide
173-194 from bovine adrenal medul ary chromaffin granules. J. biol. Chem. 271:28533-28540.
12-lugardon, K. et al., 2000, antibacterial and antifungal activities of vasostatin-1, the n-terminal fragment of
chromogranin a. J. biol. Chem. 275:10745-10753.
13-Zhang, D. et al., 2009, two chromogranin a-derived peptidesinduce calcium entryin human neutrophils by
calmodulin-regulated calcium independent phospholipase a2. Plos one 4:e4501.
14-Metz-boutigue, M. h. et al., 2003, innate immunity : involvement of new neuropeptides. trends Microbiol. 11 :585-
15-Kieffer, a. e. et al., 2003, the n- and C-terminal fragments of ubiquitin are important for the antimicrobial activities. faseb J. 10.1096/fj.02-0699fje.
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