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ISM2 UMR 7313 - Equipe Biosciences Aix Marseille Université
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.
Chronic cerebral ischemia with a notable long-term cessation of blood supply to the brain tissues leads to sensorimotor defects and short- and long-term memory problems. Neuroprotective agents are used in an attempt to save ischemic neurons from necrosis and apoptosis, such as the antioxidant agent Eucalyptus. Numerous studies have demonstrated the involvement of the renin-angiotensin system in the initiation and progression of cardiovascular and neurodegenerative diseases. Candesartan is a drug that acts as an angiotensin II receptor 1 blocker. We established a rat model exhibiting sensorimotor and cognitive impairments due to chronic cerebral ischemia induced by the ligation of the right common carotid artery. Wistar male rats were randomly divided into five groups: Sham group, Untreated Ligated group, Ischemic group treated with Eucalyptus (500 mg/kg), Ischemic group treated with Candesartan (0.5 mg/kg), and Ischemic group treated with a combination of Eucalyptus and Candesartan. To evaluate the sensorimotor disorders, we performed the beam balance test, the beam walking test, and the modified sticky test. Moreover, the object recognition test and the Morris water maze test were performed to assess the memory disorders of the rats. The infarct rat brain regions were subsequently stained using the triphenyltetrazolium chloride staining technique. The rats in the Sham group had normal sensorimotor and cognitive functions without the appearance of microscopic ischemic brain lesions. In parallel, the untreated Ischemic group showed severe impaired neurological functions with the presence of considerable brain infarctions. The treatment of the Ischemic group with a combination of both Eucalyptus and Candesartan was more efficient in improving the sensorimotor and cognitive deficits (p < 0.001) than the treatment with Eucalyptus or Candesartan alone (p < 0.05), by the comparison to the non-treated Ischemic group. Our study shows that the combination of Eucalyptus and Candesartan could decrease ischemic brain injury and improve neurological outcomes.
Christine Trabolsi; Wafaa Takash Chamoun; Akram Hijazi; Cendrine Nicoletti; Marc Maresca; Mohamad Nasser. Study of Neuroprotection by a Combination of the Biological Antioxidant (Eucalyptus Extract) and the Antihypertensive Drug Candesartan against Chronic Cerebral Ischemia in Rats. Molecules 2021, 26, 839 .
AMA StyleChristine Trabolsi, Wafaa Takash Chamoun, Akram Hijazi, Cendrine Nicoletti, Marc Maresca, Mohamad Nasser. Study of Neuroprotection by a Combination of the Biological Antioxidant (Eucalyptus Extract) and the Antihypertensive Drug Candesartan against Chronic Cerebral Ischemia in Rats. Molecules. 2021; 26 (4):839.
Chicago/Turabian StyleChristine Trabolsi; Wafaa Takash Chamoun; Akram Hijazi; Cendrine Nicoletti; Marc Maresca; Mohamad Nasser. 2021. "Study of Neuroprotection by a Combination of the Biological Antioxidant (Eucalyptus Extract) and the Antihypertensive Drug Candesartan against Chronic Cerebral Ischemia in Rats." Molecules 26, no. 4: 839.
The emergence of superbugs developing resistance to antibiotics and the resurgence of microbial infections have led scientists to start an antimicrobial arms race. In this context, we have previously identified an active RiPP, the Ruminococcin C1, naturally produced byRuminococcus gnavusE1, a symbiont of the healthy human intestinal microbiota. This RiPP, subclassified as a sactipeptide, requires the host digestive system to become active against pathogenic Clostridia and multidrug-resistant strains. Here we report its unique compact structure on the basis of four intramolecular thioether bridges with reversed stereochemistry introduced posttranslationally by a specific radical-SAM sactisynthase. This structure confers to the Ruminococcin C1 important clinical properties including stability to digestive conditions and physicochemical treatments, a higher affinity for bacteria than simulated intestinal epithelium, a valuable activity at therapeutic doses on a range of clinical pathogens, mediated by energy resources disruption, and finally safety for human gut tissues.
Clarisse Roblin; Steve Chiumento; Olivier Bornet; Matthieu Nouailler; Christina S. Müller; Katy Jeannot; Christian Basset; Sylvie Kieffer-Jaquinod; Yohann Couté; Stéphane Torelli; Laurent Le Pape; Volker Schünemann; Hamza Olleik; Bruno De La Villeon; Philippe Sockeel; Eric Di Pasquale; Cendrine Nicoletti; Nicolas Vidal; Leonora Poljak; Olga Iranzo; Thierry Giardina; Michel Fons; Estelle Devillard; Patrice Polard; Marc Maresca; Josette Perrier; Mohamed Atta; Françoise Guerlesquin; Mickael Lafond; Victor Duarte. The unusual structure of Ruminococcin C1 antimicrobial peptide confers clinical properties. Proceedings of the National Academy of Sciences 2020, 117, 19168 -19177.
AMA StyleClarisse Roblin, Steve Chiumento, Olivier Bornet, Matthieu Nouailler, Christina S. Müller, Katy Jeannot, Christian Basset, Sylvie Kieffer-Jaquinod, Yohann Couté, Stéphane Torelli, Laurent Le Pape, Volker Schünemann, Hamza Olleik, Bruno De La Villeon, Philippe Sockeel, Eric Di Pasquale, Cendrine Nicoletti, Nicolas Vidal, Leonora Poljak, Olga Iranzo, Thierry Giardina, Michel Fons, Estelle Devillard, Patrice Polard, Marc Maresca, Josette Perrier, Mohamed Atta, Françoise Guerlesquin, Mickael Lafond, Victor Duarte. The unusual structure of Ruminococcin C1 antimicrobial peptide confers clinical properties. Proceedings of the National Academy of Sciences. 2020; 117 (32):19168-19177.
Chicago/Turabian StyleClarisse Roblin; Steve Chiumento; Olivier Bornet; Matthieu Nouailler; Christina S. Müller; Katy Jeannot; Christian Basset; Sylvie Kieffer-Jaquinod; Yohann Couté; Stéphane Torelli; Laurent Le Pape; Volker Schünemann; Hamza Olleik; Bruno De La Villeon; Philippe Sockeel; Eric Di Pasquale; Cendrine Nicoletti; Nicolas Vidal; Leonora Poljak; Olga Iranzo; Thierry Giardina; Michel Fons; Estelle Devillard; Patrice Polard; Marc Maresca; Josette Perrier; Mohamed Atta; Françoise Guerlesquin; Mickael Lafond; Victor Duarte. 2020. "The unusual structure of Ruminococcin C1 antimicrobial peptide confers clinical properties." Proceedings of the National Academy of Sciences 117, no. 32: 19168-19177.
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.
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.
: 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.
Acylase 1 was investigated at the cellular level in the rat small intestine along the enterocyte-differentiation axis. As confirmed by microscopic analysis, villus tip cells and crypt cells of rat jejunal mucosa were successfully separated using the Weiser method. The proliferating undifferentiated crypt cells showed much higher ACY 1 activity levels than the villus cells, with a 6.4-fold decrease as the cells migrated and differentiated along the crypt-villus axis. RT-PCR studies on mRNA extracted from isolated cells showed that ACY 1 mRNA was mainly expressed in crypt cells, reaching levels that were 12-fold higher than those recorded in other cell types along the whole enterocyte differentiation axis. It was concluded that the expression of ACY 1 in the intestinal crypt cells is regulated at the mRNA level. Immunohistochemistry revealed the expression of ACY 1 in the absorbing lineage cells from the ileal and colonic crypts and the absence of ACY 1 in the mucus producing goblet cells. These findings proposed ACY 1 as a new marker transcript for absorbing cells of intestinal crypt, which can be used to monitor the process of intestinal N-alpha-acetylated protein metabolism.
Natacha Cigna; Cendrine Nicoletti; Anne Durand; Jean Claude Chaix; Thierry Giardina; Josette Perrier. Acylase 1 expression in rat intestinal crypt–villus axis. Cell Biology International 2007, 31, 966 -973.
AMA StyleNatacha Cigna, Cendrine Nicoletti, Anne Durand, Jean Claude Chaix, Thierry Giardina, Josette Perrier. Acylase 1 expression in rat intestinal crypt–villus axis. Cell Biology International. 2007; 31 (9):966-973.
Chicago/Turabian StyleNatacha Cigna; Cendrine Nicoletti; Anne Durand; Jean Claude Chaix; Thierry Giardina; Josette Perrier. 2007. "Acylase 1 expression in rat intestinal crypt–villus axis." Cell Biology International 31, no. 9: 966-973.