Nowadays the presence of agents and pathogens in food supply chain that developed antimicrobial resistance (AMR) is an increasing problem for human health. World Health Organization (WHO) defined the antimicrobial resistance as one of the top five public health threats. Antimicrobial resistance can be transmitted from microorganisms to microorganisms in different ways (phages, trasposoms and plasmins), resulting in horizontal gene transfer (HGT). It is important to highlight that antimicrobials are used in all sectors of food supply chain: as antifungal and pesticides to maximise the crops; as antibiotics in animal production and in aquaculture; as preservatives for the shelves food life; as antiviral agents in functional foods. The escalating emergence of AMR in food supply chain make it necessary the search for new antimicrobial compounds. In this context, nature can be a potent source of inspiration for the development of new and innovative antimicrobials. The focus of this PhD thesis was to contribute to the expansion of the arsenal of antifungal, antibacterial and antiviral compounds by paying particular attention to natural and nature-inspired compounds. Two different strategies were followed. The first strategy was based on the development of a synthetic approach to build novel antifungal and antibacterial agents. In the field of antifungals, we concentrated on the design and synthesis of a collection of strobilurin derivatives. Strobilurins, or more correctly quinone outside inhibitors (QoI), originate from a natural compound discovered in 1977 and cover almost 20% of the fungicide’s world sales. In particular, this class of compounds is used against Pyricularia oryzae, a rice blast responsible of the biggest part of losses of global production. In the last decades, several resistance mechanisms, based on the mutation in the target site gene of strobilurins, have been developed. Mutation G143A is by far the most important mechanism of resistance and has a strong effect on the activity of QoIs. For this reason, our strategy was based on the development of multi-target compounds, which can improve the efficacy and overcame the resistance, acting simultaneously on multiple, well-known and validated targets. In fact, starting from strobilurins’ pharmacophore, we created new analogues connecting in different position the pharmacophore of another class of antifungal agents, e.g. succinate-dehydrogenase inhibitors. The novel compounds were tested against wild-type and resistant-strobilurin strains of P. oryzae. In silico modeling studies gave important information about the structural requirement of the new antifungal compounds. About antibacterial and preservatives agents, we focused on stilbenoids. Stilbenoids belong to the class of polyphenols, in which resveratrol is the most studied compound. They are produced by plants as means of defence against pathogens invasion and stress factors. Several studies showed their surprising biological activities, such as anticancer, antioxidant, neuroprotective and antimicrobial. In particular, we investigated dimers of resveratrol such as dehydro--viniferin and dehydro--viniferin, carrying out structure-activity-relationship (SAR) studies. Moreover, we modified the scaffold of monomeric stilbenoids with the aim of obtaining compounds able to overcome the outer membrane of Gram-negative bacteria. The second approach was directed to extraction and isolation of bioactive natural products from vegetal matrices. In order to give our contribution on the research against COVID-19, we focused on grapefruit seeds, inspired by the known antiviral activities of grapefruit seeds extract (GSE). A small collection of extracts and five pure isolated secondary metabolites, belonging to the class of limonoids and flavonoid glycosides, were isolated and investigated for the ability to counteract SARS-CoV-2 infection, by studying both the potential antiviral effect as well as the ability to reduce uncontrolled oxidative stress response.

NATURAL AND NATURE-INSPIRED COMPOUNDS AS ANTIMICROBIAL AGENTS: EXTRACTION, SYNTHESIS AND BIOLOGICAL INVESTIGATION / G. Catinella ; tutor: S. Dallavalle; coordinatore: A. Pagliarini. - : . Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2021 Dec 03. ((34. ciclo, Anno Accademico 2021.

NATURAL AND NATURE-INSPIRED COMPOUNDS AS ANTIMICROBIAL AGENTS: EXTRACTION, SYNTHESIS AND BIOLOGICAL INVESTIGATION

G. Catinella
2021

Abstract

Nowadays the presence of agents and pathogens in food supply chain that developed antimicrobial resistance (AMR) is an increasing problem for human health. World Health Organization (WHO) defined the antimicrobial resistance as one of the top five public health threats. Antimicrobial resistance can be transmitted from microorganisms to microorganisms in different ways (phages, trasposoms and plasmins), resulting in horizontal gene transfer (HGT). It is important to highlight that antimicrobials are used in all sectors of food supply chain: as antifungal and pesticides to maximise the crops; as antibiotics in animal production and in aquaculture; as preservatives for the shelves food life; as antiviral agents in functional foods. The escalating emergence of AMR in food supply chain make it necessary the search for new antimicrobial compounds. In this context, nature can be a potent source of inspiration for the development of new and innovative antimicrobials. The focus of this PhD thesis was to contribute to the expansion of the arsenal of antifungal, antibacterial and antiviral compounds by paying particular attention to natural and nature-inspired compounds. Two different strategies were followed. The first strategy was based on the development of a synthetic approach to build novel antifungal and antibacterial agents. In the field of antifungals, we concentrated on the design and synthesis of a collection of strobilurin derivatives. Strobilurins, or more correctly quinone outside inhibitors (QoI), originate from a natural compound discovered in 1977 and cover almost 20% of the fungicide’s world sales. In particular, this class of compounds is used against Pyricularia oryzae, a rice blast responsible of the biggest part of losses of global production. In the last decades, several resistance mechanisms, based on the mutation in the target site gene of strobilurins, have been developed. Mutation G143A is by far the most important mechanism of resistance and has a strong effect on the activity of QoIs. For this reason, our strategy was based on the development of multi-target compounds, which can improve the efficacy and overcame the resistance, acting simultaneously on multiple, well-known and validated targets. In fact, starting from strobilurins’ pharmacophore, we created new analogues connecting in different position the pharmacophore of another class of antifungal agents, e.g. succinate-dehydrogenase inhibitors. The novel compounds were tested against wild-type and resistant-strobilurin strains of P. oryzae. In silico modeling studies gave important information about the structural requirement of the new antifungal compounds. About antibacterial and preservatives agents, we focused on stilbenoids. Stilbenoids belong to the class of polyphenols, in which resveratrol is the most studied compound. They are produced by plants as means of defence against pathogens invasion and stress factors. Several studies showed their surprising biological activities, such as anticancer, antioxidant, neuroprotective and antimicrobial. In particular, we investigated dimers of resveratrol such as dehydro--viniferin and dehydro--viniferin, carrying out structure-activity-relationship (SAR) studies. Moreover, we modified the scaffold of monomeric stilbenoids with the aim of obtaining compounds able to overcome the outer membrane of Gram-negative bacteria. The second approach was directed to extraction and isolation of bioactive natural products from vegetal matrices. In order to give our contribution on the research against COVID-19, we focused on grapefruit seeds, inspired by the known antiviral activities of grapefruit seeds extract (GSE). A small collection of extracts and five pure isolated secondary metabolites, belonging to the class of limonoids and flavonoid glycosides, were isolated and investigated for the ability to counteract SARS-CoV-2 infection, by studying both the potential antiviral effect as well as the ability to reduce uncontrolled oxidative stress response.
DALLAVALLE, SABRINA
PAGLIARINI, ANTONELLA
Settore CHIM/06 - Chimica Organica
NATURAL AND NATURE-INSPIRED COMPOUNDS AS ANTIMICROBIAL AGENTS: EXTRACTION, SYNTHESIS AND BIOLOGICAL INVESTIGATION / G. Catinella ; tutor: S. Dallavalle; coordinatore: A. Pagliarini. - : . Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2021 Dec 03. ((34. ciclo, Anno Accademico 2021.
Doctoral Thesis
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/887211
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