Innovations dans les composés ammonium bi-quaternaires : conception d’agents antimicrobiens et anticancéreux à base de benzimidazolium
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- bis-benzimidazolium
- ammonium bi-quaternaire
- bis-quaternary
- ammonium compounds antimicrobial agents
- anti-biofilm agents
- anticancer agents
- membrane permeabilization
- mitochondria targeting
- depolarization
- liposomes
- transmembrane transport
- agents antimicrobiens
- agents anti-biofilm
- agents anticancéreux
- perméabilisation membranaire
- ciblage des mitochondries
- dépolarisation
- liposomes
- transport transmembranaire
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Les progrès en biologie moléculaire ont conduit à la découverte d'une large gamme de petits peptides cationiques amphiphiles, appelés peptides antimicrobiens (AMPs). Ces peptides font partie du système immunitaire inné des organismes multicellulaires et présentent une diversité d’effets contre les bactéries, les champignons, les virus, les protozoaires et les cellules cancéreuses. L'attraction électrostatique entre les composants chargés négativement des membranes cellulaires bactériennes et cancéreuses et les AMPs chargés positivement joue un rôle majeur dans la perturbation sélective de ces membranes, conduisant à la mort cellulaire. Les AMPs ont montré un potentiel prometteur pour lutter contre les maladies infectieuses et le cancer qui demeurent des causes majeures de morbidité humaine, exacerbées par l'émergence rapide de résistances aux agents chimiothérapeutiques conventionnels. Cependant, les limitations intrinsèques des AMPs restreignent leur utilisation clinique, ce qui a suscité un intérêt croissant pour le développement d'analogues synthétiques. Cette thèse vise donc à examiner le potentiel de petites molécules imitant les propriétés des AMPs en tant qu’agents antimicrobiens et anticancéreux, en se concentrant sur leur conception et leur activité biologique. Le projet initial vise à concevoir et optimiser des agents amphiphiles bis-cationiques à base d’ammonium quaternaire, pour combattre la résistance antimicrobienne et la persistance bactérienne associée aux biofilms. Plusieurs séries de composés à base de bis-benzimidazolium ont été synthétisées, variant en hydrophobie, rigidité et densité de charge. La relation structure-activité a été déterminée en testant ces composés contre des souches multirésistantes (SARM, ERV, E. coli et C. albicans). La sélectivité des composés a également été évaluée en exposant des globules rouges humains aux analogues de bis-benzimidazolium. Enfin nous avons mesuré l’efficacité anti-biofilm des candidats les plus prometteurs et avons testé leur capacité à contrer le développement de résistances chez les SARM et les E. coli. Leur efficacité nous a conduit à explorer le mécanisme d'action des analogues de bis-benzimidazolium. Les AMPs exerçant leurs effets biocides en perturbant les bicouches lipidiques, nous nous sommes donc concentrés sur l’impact de nos composés sur l'intégrité des membranes. Pour cela nous avons utilisé des modèles membranaires pour étudier le processus de perméabilisation de nos composés. La perméabilisation des membranes a été associée à un mécanisme de dépolarisation de la membrane bactérienne. Enfin, nous avons exploré le potentiel anticancéreux des composés amphiphiles bis-cationiques en évaluant leur efficacité contre un modèle du cancer du pancréas et en étudiant leur mécanisme d'action. Les études ont révélé que leur structure leur permettait de cibler et de perméabiliser sélectivement les membranes des cellules cancéreuses et de s'accumuler au niveau des mitochondries, entraînant la dépolarisation de la membrane mitochondriale. De plus, leur effet perméabilisant facilite le passage transmembranaire de la metformine, un médicament connu pour avoir un effet anticancéreux, mais entravé par sa forte hydrophilie qui limite sa biodisponibilité. La combinaison de la metformine avec nos composés a conduit à un effet synergique contre les cellules cancéreuses pancréatiques. Cette thèse contribue à faire avancer la recherche sur de nouveaux agents antimicrobiens et anticancéreux efficaces en apportant une meilleure compréhension de l'action des petites molécules amphiphiles cationiques à base d’ammonium bis-quaternaire, afin de répondre aux défis majeurs du traitement des maladies infectieuses et du cancer.
Advances in molecular biology have led to the discovery of a wide range of small cationic amphiphilic peptides, known as antimicrobial peptides (AMPs). These peptides are part of the innate immune system of multicellular organisms and exhibit a diverse range of effects against bacteria, fungi, viruses, protozoa and cancer cells. The electrostatic attraction between the negatively charged components of bacterial and cancer cell membranes and the positively charged AMPs plays a major role in the selective disruption of these membranes, leading to cell death. As infectious diseases and cancer remain leading causes of human morbidity, exacerbated by the rapid emergence of resistance to conventional chemotherapeutic agents, AMPs have shown promise due to their broad-spectrum activity. However, their intrinsic limitations have restricted their clinical use and spurred significant interest in developing synthetic analogues. This thesis aims to examine the potential of small molecules that mimic the properties of AMPs as antimicrobial and anticancer agents, focusing on their design and biological activity. The project initially focuses on designing and optimizing bis-cationic amphiphilic agents based on quaternary ammoniums salts, to address antimicrobial resistance and biofilm-related bacterial persistence. Several series of bis-benzimidazolium based compounds were synthesized, varying in hydrophobicity, rigidity and charge density. The structure-activity relationship was determined by testing the compounds against multidrug-resistant strains (MRSA, VRE, E. coli, and C. albicans). The selectivity of the compounds was also assessed by exposing human red blood cells to the bis-benzimidazolium analogues. Additionally, we measured the anti-biofilm efficacy of the most promising candidates and tested their ability to counter resistance development in MRSA and E. coli strains. Their strong activity prompted us to investigate the mechanism of action of the bis-benzimidazolium analogues. Given that AMPs exert their biocidal effects through lipid bilayer disruption, we focused on the impact of our compounds on membrane integrity. Therefore, we used membrane models to study the permeabilization process of our compounds. Membrane disruption was associated with the depolarization of the bacterial membrane.Finally, we explored the potential of bis-cationic amphiphilic compounds as anticancer agents. We evaluated these compounds for their chemotherapeutic efficacy against a model of pancreatic cancer and investigated their mechanism of action. Studies revealed that their structure allowed for them to selectively target and permeabilize cancer cell membranes and accumulate in mitochondria, leading to depolarization of the mitochondrial membrane. Moreover, their permeabilizing effect facilitated transmembrane passage of metformin, a drug known for its anticancer effect but hindered by its high hydrophilicity which limits its bioavailability. The combination of metformin with our compounds resulted in a synergistic effect against pancreatic cancer cells. This thesis contributes to the ongoing research for effective antimicrobials and anticancer agents by providing a better understanding of the action of cationic amphiphilic small molecules based on bis-quaternary ammonium salts, addressing key challenges in the treatment of infectious diseases and cancer.
Advances in molecular biology have led to the discovery of a wide range of small cationic amphiphilic peptides, known as antimicrobial peptides (AMPs). These peptides are part of the innate immune system of multicellular organisms and exhibit a diverse range of effects against bacteria, fungi, viruses, protozoa and cancer cells. The electrostatic attraction between the negatively charged components of bacterial and cancer cell membranes and the positively charged AMPs plays a major role in the selective disruption of these membranes, leading to cell death. As infectious diseases and cancer remain leading causes of human morbidity, exacerbated by the rapid emergence of resistance to conventional chemotherapeutic agents, AMPs have shown promise due to their broad-spectrum activity. However, their intrinsic limitations have restricted their clinical use and spurred significant interest in developing synthetic analogues. This thesis aims to examine the potential of small molecules that mimic the properties of AMPs as antimicrobial and anticancer agents, focusing on their design and biological activity. The project initially focuses on designing and optimizing bis-cationic amphiphilic agents based on quaternary ammoniums salts, to address antimicrobial resistance and biofilm-related bacterial persistence. Several series of bis-benzimidazolium based compounds were synthesized, varying in hydrophobicity, rigidity and charge density. The structure-activity relationship was determined by testing the compounds against multidrug-resistant strains (MRSA, VRE, E. coli, and C. albicans). The selectivity of the compounds was also assessed by exposing human red blood cells to the bis-benzimidazolium analogues. Additionally, we measured the anti-biofilm efficacy of the most promising candidates and tested their ability to counter resistance development in MRSA and E. coli strains. Their strong activity prompted us to investigate the mechanism of action of the bis-benzimidazolium analogues. Given that AMPs exert their biocidal effects through lipid bilayer disruption, we focused on the impact of our compounds on membrane integrity. Therefore, we used membrane models to study the permeabilization process of our compounds. Membrane disruption was associated with the depolarization of the bacterial membrane.Finally, we explored the potential of bis-cationic amphiphilic compounds as anticancer agents. We evaluated these compounds for their chemotherapeutic efficacy against a model of pancreatic cancer and investigated their mechanism of action. Studies revealed that their structure allowed for them to selectively target and permeabilize cancer cell membranes and accumulate in mitochondria, leading to depolarization of the mitochondrial membrane. Moreover, their permeabilizing effect facilitated transmembrane passage of metformin, a drug known for its anticancer effect but hindered by its high hydrophilicity which limits its bioavailability. The combination of metformin with our compounds resulted in a synergistic effect against pancreatic cancer cells. This thesis contributes to the ongoing research for effective antimicrobials and anticancer agents by providing a better understanding of the action of cationic amphiphilic small molecules based on bis-quaternary ammonium salts, addressing key challenges in the treatment of infectious diseases and cancer.
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