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The world is on the verge of a major antibiotic crisis as the emergence of resistant bacteria is increasing, and very few novel molecules have been discovered since the 1960s. In this context, scientists have been exploring alternatives to conventional antibiotics, such as ribosomally synthesized and post-translationally modified peptides (RiPPs). Interestingly, the highly potent in vitro antibacterial activity and safety of ruminococcin C1, a recently discovered RiPP belonging to the sactipeptide subclass, has been demonstrated. The present results show that ruminococcin C1 is efficient at curing infection and at protecting challenged mice from Clostridium perfringens with a lower dose than the conventional antibiotic vancomycin. Moreover, antimicrobial peptide (AMP) is also effective against this pathogen in the complex microbial community of the gut environment, with a selective impact on a few bacterial genera, while maintaining a global homeostasis of the microbiome. In addition, ruminococcin C1 exhibits other biological activities that could be beneficial for human health, as well as other fields of applications. Overall, this study, by using an in vivo infection approach, confirms the antimicrobial clinical potential and highlights the multiple functional properties of ruminococcin C1, thus extending its therapeutic interest.
Clarisse Roblin; Steve Chiumento; Cédric Jacqueline; Eric Pinloche; Cendrine Nicoletti; Hamza Olleik; Elise Courvoisier-Dezord; Agnès Amouric; Christian Basset; Louis Dru; Marie Ollivier; Aurélie Bogey-Lambert; Nicolas Vidal; Mohamed Atta; Marc Maresca; Estelle Devillard; Victor Duarte; Josette Perrier; Mickael Lafond. The Multifunctional Sactipeptide Ruminococcin C1 Displays Potent Antibacterial Activity In Vivo as Well as Other Beneficial Properties for Human Health. International Journal of Molecular Sciences 2021, 22, 3253 .
AMA StyleClarisse Roblin, Steve Chiumento, Cédric Jacqueline, Eric Pinloche, Cendrine Nicoletti, Hamza Olleik, Elise Courvoisier-Dezord, Agnès Amouric, Christian Basset, Louis Dru, Marie Ollivier, Aurélie Bogey-Lambert, Nicolas Vidal, Mohamed Atta, Marc Maresca, Estelle Devillard, Victor Duarte, Josette Perrier, Mickael Lafond. The Multifunctional Sactipeptide Ruminococcin C1 Displays Potent Antibacterial Activity In Vivo as Well as Other Beneficial Properties for Human Health. International Journal of Molecular Sciences. 2021; 22 (6):3253.
Chicago/Turabian StyleClarisse Roblin; Steve Chiumento; Cédric Jacqueline; Eric Pinloche; Cendrine Nicoletti; Hamza Olleik; Elise Courvoisier-Dezord; Agnès Amouric; Christian Basset; Louis Dru; Marie Ollivier; Aurélie Bogey-Lambert; Nicolas Vidal; Mohamed Atta; Marc Maresca; Estelle Devillard; Victor Duarte; Josette Perrier; Mickael Lafond. 2021. "The Multifunctional Sactipeptide Ruminococcin C1 Displays Potent Antibacterial Activity In Vivo as Well as Other Beneficial Properties for Human Health." International Journal of Molecular Sciences 22, no. 6: 3253.
The biological activities of berberine, a natural plant molecule, are known to be affected by structural modifications, mostly at position 9 and/or 13. A series of new 13-substituted berberine derivatives were synthesized and evaluated in term of antimicrobial activity using various microorganisms associated to human diseases. Contrarily to the original molecule berberine, several derivatives were found strongly active in microbial sensitivity tests against Mycobacterium, Candida albicans and Gram-positive bacteria, including naïve or resistant Bacillus cereus, Staphylococcus aureus and Streptococcus pyogenes with minimal inhibitory concentration (MIC) of 3.12 to 6.25 µM. Among the various Gram-negative strains tested, berberine’s derivatives were only found active on Helicobacter pylori and Vibrio alginolyticus (MIC values of 1.5–3.12 µM). Cytotoxicity assays performed on human cells showed that the antimicrobial berberine derivatives caused low toxicity resulting in good therapeutic index values. In addition, a mechanistic approach demonstrated that, contrarily to already known berberine derivatives causing either membrane permeabilization, DNA fragmentation or interacting with FtsZ protein, active derivatives described in this study act through inhibition of the synthesis of peptidoglycan or RNA. Overall, this study shows that these new berberine derivatives can be considered as potent and safe anti-bacterial agents active on human pathogenic microorganisms, including ones resistant to conventional antibiotics.
Hamza Olleik; Taher Yacoub; Laurent Hoffer; Senankpon Martial Gnansounou; Kehna Benhaiem-Henry; Cendrine Nicoletti; Malika Mekhalfi; Valerie Pique; Josette Perrier; Akram Hijazi; Elias Baydoun; Josette Raymond; Philippe Piccerelle; Marc Maresca; Maxime Robin. Synthesis and Evaluation of the Antibacterial Activities of 13-Substituted Berberine Derivatives. Antibiotics 2020, 9, 381 .
AMA StyleHamza Olleik, Taher Yacoub, Laurent Hoffer, Senankpon Martial Gnansounou, Kehna Benhaiem-Henry, Cendrine Nicoletti, Malika Mekhalfi, Valerie Pique, Josette Perrier, Akram Hijazi, Elias Baydoun, Josette Raymond, Philippe Piccerelle, Marc Maresca, Maxime Robin. Synthesis and Evaluation of the Antibacterial Activities of 13-Substituted Berberine Derivatives. Antibiotics. 2020; 9 (7):381.
Chicago/Turabian StyleHamza Olleik; Taher Yacoub; Laurent Hoffer; Senankpon Martial Gnansounou; Kehna Benhaiem-Henry; Cendrine Nicoletti; Malika Mekhalfi; Valerie Pique; Josette Perrier; Akram Hijazi; Elias Baydoun; Josette Raymond; Philippe Piccerelle; Marc Maresca; Maxime Robin. 2020. "Synthesis and Evaluation of the Antibacterial Activities of 13-Substituted Berberine Derivatives." Antibiotics 9, no. 7: 381.
Helicobacterpylori is one of the most prevalent pathogens colonizing 50% of the world’s population and causing gastritis and gastric cancer. Even with triple and quadruple antibiotic therapies, H. pylori shows increased prevalence of resistance to conventional antibiotics and treatment failure. Due to their pore-forming activity, antimicrobial peptides (AMP) are considered as a good alternative to conventional antibiotics, particularly in the case of resistant bacteria. In this study, temporin-SHa (a frog AMP) and its analogs obtained by Gly to Ala substitutions were tested against H. pylori. Results showed differences in the antibacterial activity and toxicity of the peptides in relation to the number and position of D-Ala substitution. Temporin-SHa and its analog NST1 were identified as the best molecules, both peptides being active on clinical resistant strains, killing 90–100% of bacteria in less than 1 h and showing low to no toxicity against human gastric cells and tissue. Importantly, the presence of gastric mucins did not prevent the antibacterial effect of temporin-SHa and NST1, NST1 being in addition resistant to pepsin. Taken together, our results demonstrated that temporin-SHa and its analog NST1 could be considered as potential candidates to treat H. pylori, particularly in the case of resistant strains.
Hamza Olleik; Elias Baydoun; Josette Perrier; Akram Hijazi; Josette Raymond; Marine Manzoni; Lucas Dupuis; Ghislain Pauleau; Yvain Goudard; Bruno De La Villéon; Géraldine Goin; Philippe Sockeel; Muhammad Iqbal Choudhary; Eric Di Pasquale; Muhammad Nadeem-Ul-Haque; Hunain Ali; Arif Iftikhar Khan; Farzana Shaheen; Marc Maresca. Temporin-SHa and Its Analogs as Potential Candidates for the Treatment of Helicobacter pylori. Biomolecules 2019, 9, 598 .
AMA StyleHamza Olleik, Elias Baydoun, Josette Perrier, Akram Hijazi, Josette Raymond, Marine Manzoni, Lucas Dupuis, Ghislain Pauleau, Yvain Goudard, Bruno De La Villéon, Géraldine Goin, Philippe Sockeel, Muhammad Iqbal Choudhary, Eric Di Pasquale, Muhammad Nadeem-Ul-Haque, Hunain Ali, Arif Iftikhar Khan, Farzana Shaheen, Marc Maresca. Temporin-SHa and Its Analogs as Potential Candidates for the Treatment of Helicobacter pylori. Biomolecules. 2019; 9 (10):598.
Chicago/Turabian StyleHamza Olleik; Elias Baydoun; Josette Perrier; Akram Hijazi; Josette Raymond; Marine Manzoni; Lucas Dupuis; Ghislain Pauleau; Yvain Goudard; Bruno De La Villéon; Géraldine Goin; Philippe Sockeel; Muhammad Iqbal Choudhary; Eric Di Pasquale; Muhammad Nadeem-Ul-Haque; Hunain Ali; Arif Iftikhar Khan; Farzana Shaheen; Marc Maresca. 2019. "Temporin-SHa and Its Analogs as Potential Candidates for the Treatment of Helicobacter pylori." Biomolecules 9, no. 10: 598.
Filamentous fungi, although producing noxious molecules such as mycotoxins, have been used to produce numerous drugs active against human diseases such as paclitaxel, statins, and penicillin, saving millions of human lives. Cyclodepsipeptides are fungal molecules with potentially adverse and positive effects. Although these peptides are not novel, comparative studies of their antimicrobial activity, toxicity, and mechanism of action are still to be identified. In this study, the fungal cyclohexadepsipeptides enniatin (ENN) and beauvericin (BEA) were assessed to determine their antimicrobial activity and cytotoxicity against human cells. Results showed that these peptides were active against Gram-positive bacteria, Mycobacterium, and fungi, but not against Gram-negative bacteria. ENN and BEA had a limited hemolytic effect, yet were found to be toxic at low doses to nucleated human cells. Both peptides also interacted with bacterial lipids, causing low to no membrane permeabilization, but induced membrane depolarization and inhibition of macromolecules synthesis. The structure-activity analysis showed that the chemical nature of the side chains present on ENN and BEA (either iso-propyl, sec-butyl, or phenylmethyl) impacts their interaction with lipids, antimicrobial action, and toxicity.
Hamza Olleik; Cendrine Nicoletti; Mickael Lafond; Elise Courvoisier-Dezord; Peiwen Xue; Akram Hijazi; Elias Baydoun; Josette Perrier; Marc Maresca. Comparative Structure-Activity Analysis of the Antimicrobial Activity, Cytotoxicity, and Mechanism of Action of the Fungal Cyclohexadepsipeptides Enniatins and Beauvericin. Toxins 2019, 11, 514 .
AMA StyleHamza Olleik, Cendrine Nicoletti, Mickael Lafond, Elise Courvoisier-Dezord, Peiwen Xue, Akram Hijazi, Elias Baydoun, Josette Perrier, Marc Maresca. Comparative Structure-Activity Analysis of the Antimicrobial Activity, Cytotoxicity, and Mechanism of Action of the Fungal Cyclohexadepsipeptides Enniatins and Beauvericin. Toxins. 2019; 11 (9):514.
Chicago/Turabian StyleHamza Olleik; Cendrine Nicoletti; Mickael Lafond; Elise Courvoisier-Dezord; Peiwen Xue; Akram Hijazi; Elias Baydoun; Josette Perrier; Marc Maresca. 2019. "Comparative Structure-Activity Analysis of the Antimicrobial Activity, Cytotoxicity, and Mechanism of Action of the Fungal Cyclohexadepsipeptides Enniatins and Beauvericin." Toxins 11, no. 9: 514.
Herein we report the identification and characterisation of two linear antimicrobial peptides (AMPs), HG2 and HG4, with activity against a wide range of multidrug resistant (MDR) bacteria, especially methicillin resistantStaphylococcus aureus(MRSA) strains, a highly problematic group of Gram-positive bacteria in the hospital and community environment. To identify the novel AMPs presented here, we employed the classifier model design, a feature extraction method using molecular descriptors for amino acids for the analysis, visualization, and interpretation of AMP activities from a rumen metagenomic dataset. This allowed for thein silicodiscrimination of active and inactive peptides in order to define a small number of promising novel lead AMP test candidates for chemical synthesis and experimental evaluation.In vitrodata suggest that the chosen AMPs are fast acting, show strong biofilm inhibition and dispersal activity and are efficacious in anin vivomodel of MRSA USA300 infection, whilst showing little toxicity to human erythrocytes and human primary cell linesex vivo. Observations from biophysical AMP-lipid-interactions and electron microscopy suggest that the newly identified peptides interact with the cell membrane and may be involved in the inhibition of other cellular processes. Amphiphilic conformations associated with membrane disruption are also observed in 3D molecular modelling of the peptides. HG2 and HG4 both preferentially bind to MRSA total lipids rather than with human cell lipids indicating that HG4 may form superior templates for safer therapeutic candidates for MDR bacterial infections.Author SummaryWe are losing our ability to treat multidrug resistant (MDR) bacteria, otherwise known as superbugs. This poses a serious global threat to human health as bacteria are increasingly acquiring resistance to antibiotics. There is therefore urgent need to intensify our efforts to develop new safer alternative drug candidates. We emphasise the usefulness of complementing wet-lab andin silicotechniques for the rapid identification of new drug candidates from environmental samples, especially antimicrobial peptides (AMPs). HG2 and HG4, the AMPs identified in our study show promise as effective therapies for the treatment of methicillin resistantStaphylococcus aureusinfections bothin vitroandin vivowhilst having little cytotoxicity against human primary cells, a step forward in the fight against MDR infections.
Linda Boniface Oyama; Hamza Olleik; Ana Carolina Nery Teixeira; Matheus M Guidini; James A Pickup; Alan R Cookson; Hannah Vallin; Toby Wilkinson; Denise Bazzolli; Jennifer Richards; Mandy Wootton; Ralf Mikut; Kai Hilpert; Marc Maresca; Josette Perrier; Matthias Hess; Hilario C Mantovani; Narcis Fernandez-Fuentes; Christopher J Creevey; Sharon A Huws. In silicoidentification of novel peptides with antibacterial activity against multidrug resistantStaphylococcus aureus. 2019, 577221 .
AMA StyleLinda Boniface Oyama, Hamza Olleik, Ana Carolina Nery Teixeira, Matheus M Guidini, James A Pickup, Alan R Cookson, Hannah Vallin, Toby Wilkinson, Denise Bazzolli, Jennifer Richards, Mandy Wootton, Ralf Mikut, Kai Hilpert, Marc Maresca, Josette Perrier, Matthias Hess, Hilario C Mantovani, Narcis Fernandez-Fuentes, Christopher J Creevey, Sharon A Huws. In silicoidentification of novel peptides with antibacterial activity against multidrug resistantStaphylococcus aureus. . 2019; ():577221.
Chicago/Turabian StyleLinda Boniface Oyama; Hamza Olleik; Ana Carolina Nery Teixeira; Matheus M Guidini; James A Pickup; Alan R Cookson; Hannah Vallin; Toby Wilkinson; Denise Bazzolli; Jennifer Richards; Mandy Wootton; Ralf Mikut; Kai Hilpert; Marc Maresca; Josette Perrier; Matthias Hess; Hilario C Mantovani; Narcis Fernandez-Fuentes; Christopher J Creevey; Sharon A Huws. 2019. "In silicoidentification of novel peptides with antibacterial activity against multidrug resistantStaphylococcus aureus." , no. : 577221.
Towards a versatile and easy method of elaboration of solid polymeric antimicrobial materials.
Belkacem Tarek Benkhaled; Slim Hadiouch; Hamza Olleik; Josette Perrier; Cedric Ysacco; Yohann Guillaneuf; Didier Gigmes; Marc Maresca; Catherine Lefay. Elaboration of antimicrobial polymeric materials by dispersion of well-defined amphiphilic methacrylic SG1-based copolymers. Polymer Chemistry 2018, 9, 3127 -3141.
AMA StyleBelkacem Tarek Benkhaled, Slim Hadiouch, Hamza Olleik, Josette Perrier, Cedric Ysacco, Yohann Guillaneuf, Didier Gigmes, Marc Maresca, Catherine Lefay. Elaboration of antimicrobial polymeric materials by dispersion of well-defined amphiphilic methacrylic SG1-based copolymers. Polymer Chemistry. 2018; 9 (22):3127-3141.
Chicago/Turabian StyleBelkacem Tarek Benkhaled; Slim Hadiouch; Hamza Olleik; Josette Perrier; Cedric Ysacco; Yohann Guillaneuf; Didier Gigmes; Marc Maresca; Catherine Lefay. 2018. "Elaboration of antimicrobial polymeric materials by dispersion of well-defined amphiphilic methacrylic SG1-based copolymers." Polymer Chemistry 9, no. 22: 3127-3141.
In addition to deoxynivalenol (DON), acetylated derivatives, i.e., 3-acetyl and 15-acetyldexynivalenol (or 3/15ADON), are present in cereals leading to exposure to these mycotoxins. Animal and human studies suggest that 3/15ADON are converted into DON after their ingestion through hydrolysis of the acetyl moiety, the site(s) of such deacetylation being still uncharacterized. We used in vitro and ex vivo approaches to study the deacetylation of 3/15ADON by enzymes and cells/tissues present on their way from the food matrix to the blood in humans. We found that luminal deacetylation by digestive enzymes and bacteria is limited. Using human cells, tissues and S9 fractions, we were able to demonstrate that small intestine and liver possess strong deacetylation capacity compared to colon and kidneys. Interestingly, in most cases, deacetylation was more efficient for 3ADON than 15ADON. Although we initially thought that carboxylesterases (CES) could be responsible for the deacetylation of 3/15ADON, the use of pure human CES1/2 and of CES inhibitor demonstrated that CES are not involved. Taken together, our original model system allowed us to identify the small intestine and the liver as the main site of deacetylation of ingested 3/15ADON in humans.
El Hassan Ajandouz; Stéphane Berdah; Vincent Moutardier; Thierry Bege; David Jérémie Birnbaum; Josette Perrier; Eric Di Pasquale; Marc Maresca. Hydrolytic Fate of 3/15-Acetyldeoxynivalenol in Humans: Specific Deacetylation by the Small Intestine and Liver Revealed Using in Vitro and ex Vivo Approaches. Toxins 2016, 8, 232 .
AMA StyleEl Hassan Ajandouz, Stéphane Berdah, Vincent Moutardier, Thierry Bege, David Jérémie Birnbaum, Josette Perrier, Eric Di Pasquale, Marc Maresca. Hydrolytic Fate of 3/15-Acetyldeoxynivalenol in Humans: Specific Deacetylation by the Small Intestine and Liver Revealed Using in Vitro and ex Vivo Approaches. Toxins. 2016; 8 (8):232.
Chicago/Turabian StyleEl Hassan Ajandouz; Stéphane Berdah; Vincent Moutardier; Thierry Bege; David Jérémie Birnbaum; Josette Perrier; Eric Di Pasquale; Marc Maresca. 2016. "Hydrolytic Fate of 3/15-Acetyldeoxynivalenol in Humans: Specific Deacetylation by the Small Intestine and Liver Revealed Using in Vitro and ex Vivo Approaches." Toxins 8, no. 8: 232.
The molecular cross talk between commensal bacteria and the gut play an important role in the maintenance of the intestinal homeostasis and general health. Here, we studied the impact of a major Gram positive anaerobic bacterium of the human gut microbiota, i.e. Ruminococcus gnavus on the glycosylation pattern and the production of intestinal mucus by the goblet cells. Our results showed that R. gnavus E1 specifically increases the expression and the glycosylation level of the intestinal glycoconjugates by goblet cells in the colonic mucosa of mono-associated mice with R. gnavus E1 as well as in human HT29-MTX cells. Such an effect was mediated through induction of the level of mRNA encoding for the major intestinal gel-forming mucin such as MUC2 and various glycosyltransferase enzymes. This study demonstrates for the first time that R. gnavus E1 possess the ability to modulate the glycosylation profile of the glycoconjugate molecules and mucus in goblet cells. This article is protected by copyright. All rights reserved.
Fabien Graziani; Ange Pujol; Cendrine Nicoletti; Samir Dou; Marc Maresca; Thierry Giardina; Michel Fons; Josette Perrier. Ruminococcus gnavus E1 modulates mucin expression and intestinal glycosylation. Journal of Applied Microbiology 2016, 120, 1403 -1417.
AMA StyleFabien Graziani, Ange Pujol, Cendrine Nicoletti, Samir Dou, Marc Maresca, Thierry Giardina, Michel Fons, Josette Perrier. Ruminococcus gnavus E1 modulates mucin expression and intestinal glycosylation. Journal of Applied Microbiology. 2016; 120 (5):1403-1417.
Chicago/Turabian StyleFabien Graziani; Ange Pujol; Cendrine Nicoletti; Samir Dou; Marc Maresca; Thierry Giardina; Michel Fons; Josette Perrier. 2016. "Ruminococcus gnavus E1 modulates mucin expression and intestinal glycosylation." Journal of Applied Microbiology 120, no. 5: 1403-1417.
: The food‐associated mycotoxin deoxynivalenol (DON) is known to affect intestinal functions. However, its effect on intestinal mucus is poorly characterized. : We analyzed the effects of DON on human goblet cells (HT29‐16E cells) and porcine intestinal explants. Results showed that subtoxic doses of DON (as low as 1 μM) decreased mucin production. qPCR analysis demonstrated that this inhibition was due to a specific decrease in the level of mRNA encoding for the intestinal membrane‐associated (MUC1) and the secreted mucins (MUC2, MUC3). Mechanistic studies demonstrated that DON effect relied on the activation of the protein kinase R and the MAP kinase p38 ultimately leading to the inhibition of the expression of resistin‐like molecule beta (RELM‐β), a known positive regulator of mucin expression. : Taken together, our results show that at low doses found in food and feed, DON is able to affect the expression and production of mucins by human and animal goblet cells. Due to the important role of mucins in the barrier function and in the interaction of commensal bacteria with the host, such effect could explain the observed modifications in the microbial diversity and the increased susceptibility to enteric infection following exposure to DON. This article is protected by copyright. All rights reserved
Philippe Pinton; Fabien Graziani; Ange Pujol; Cendrine Nicoletti; Océane Paris; Pauline Ernouf; Eric Di Pasquale; Josette Perrier; Isabelle Oswald; Marc Maresca. Deoxynivalenol inhibits the expression by goblet cells of intestinal mucins through a PKR and MAP kinase dependent repression of the resistin-like molecule β. Molecular Nutrition & Food Research 2015, 59, 1076 -1087.
AMA StylePhilippe Pinton, Fabien Graziani, Ange Pujol, Cendrine Nicoletti, Océane Paris, Pauline Ernouf, Eric Di Pasquale, Josette Perrier, Isabelle Oswald, Marc Maresca. Deoxynivalenol inhibits the expression by goblet cells of intestinal mucins through a PKR and MAP kinase dependent repression of the resistin-like molecule β. Molecular Nutrition & Food Research. 2015; 59 (6):1076-1087.
Chicago/Turabian StylePhilippe Pinton; Fabien Graziani; Ange Pujol; Cendrine Nicoletti; Océane Paris; Pauline Ernouf; Eric Di Pasquale; Josette Perrier; Isabelle Oswald; Marc Maresca. 2015. "Deoxynivalenol inhibits the expression by goblet cells of intestinal mucins through a PKR and MAP kinase dependent repression of the resistin-like molecule β." Molecular Nutrition & Food Research 59, no. 6: 1076-1087.