Isolation, Identification, Modification, and Biological Analysis of extracts of A. Mexicana

Argemone mexicana is a member of the Papaveraceae family of plants that has been used for centuries in traditional medicine by indigenous communities in Mexico and the United States. Through a collaborative project, we have explored separation of key components of the seeds and leaves of this plant to isolate the source of their biological activity. We have already identified two key molecules which give this plant anti-microbial properties against the gram-positive bacteria. Furthermore, we have chemically modified one of these molecules to observe variations on activity. We hope this leads to the discovery of new antibiotic drugs

Identifying Antimicrobial Phytocompounds to Combat ISS Superbugs

The isolation, or creation, of novel antimicrobial agents is currently at the forefront of modern healthcare due to the stark decrease in antimicrobial drug development in recent years and due to the increasing rise of superbugs, or microorganisms that are resistant to more than one type of antimicrobial treatment, which are predicted by 2050 to cause 10 million deaths/year. In addition to being a terrestrial cause for concern, antimicrobial resistant microbes are also a threat to the health of the individuals on the International Space Station (ISS). According to recent studies, a diverse population of bacteria and fungi, including several opportunistic pathogens, have colonized the ISS, and many of these strains have been found to possess antimicrobial resistance genes. Therefore, our research is focused on testing bacterial and fungal pathogens that have been isolated from the ISS against methanolic extracts from different medicinal plants, such as Argemone mexicana and Curcuma longa. Additionally, from previous work in our lab (https://doi.org/10.1371/journal.pone.0249704), we have identified several antibacterial compounds in A. mexicana and are attempting to determine the distribution of these phytocompounds (berberine, chelerythrine, sanguinarine) in the plant using quantitative chemistry techniques. This work highlights the importance of plants as an invaluable pharmaceutical resource at a time when antimicrobial drug discovery has plateaued

Characterizing the Cytotoxic Effects and Several Antimicrobial Phytocompounds of \u3ci\u3eArgemone mexicana\u3c/i\u3e

Commonly called the Mexican prickly poppy, Argemone mexicana is a stress-resistant member of the Papaveraceae family of plants that has been used in traditional medicine for centuries by indigenous communities in Mexico and Western parts of the United States. This plant has been exploited to treat a wide variety of ailments, with reported antimicrobial and antioxidant properties, as well as cytotoxic effects against some human cancer cell lines. Due to its various therapeutic uses and its abundance of secondary metabolites, A. mexicana has great potential as a drug discovery candidate. Herein, the cytotoxic activities of different parts (seeds, leaves, inner vs. outer roots) of the plant from methanol or hexane extracts are preliminarily characterized against cells of seven unique organisms. When comparing 1 mg of each sample normalized to background solvent alone, A. mexicana methanol outer root and leaf extracts possessed the strongest antimicrobial activity, with greatest effects against the Gram-positive bacteria tested, and less activity against the Gram-negative bacteria and fungi tested. Additionally, the outer root methanol and seed hexane extracts displayed pronounced inhibitory effects against human colon cancer cells. Quantification of c-MYC (oncogene) and APC (tumor suppressor) mRNA levels help elucidate how the A. mexicana root methanol extract may be affecting colon cancer cells. After ultra-performance liquid chromatography coupled with mass spectrometry and subsequent nuclear magnetic resonance analysis of the root and leaf methanol fractions, two main antibacterial compounds, chelerythrine and berberine, have been identified. The roots were found to possess both phytocompounds, while the leaf lacked chelerythrine

Synthesis and optimization of a library of small molecule inhibitors of ricin toxin A

textRicin is a potent cyctotoxin with no known antidote. Chapter 1 provides background and context for this thesis, which is primarily focused on probing the active site of Ricin toxin A (RTA). Relevant information about Ricin, its use, method of action, and noteworthy contributions towards the discovery of Ricin A chain inhibitors are provided. Furthermore, a brief description of the assays used by our collaborators to monitor RTA inhibition is provided. Additionally, a great deal of this thesis pertains to a particular heterocycle, pterin, and thus the remainder of Chapter 1 is dedicated to pterins, their physical properties, biological relevance, and selected reports of pterin chemistry. Chapter 2 details preliminary research focused on the use of nucleic acid-based platforms as RTA inhibitors. Two specific nucleic acids were chosen, adenine and guanine, and the chapter is split to address them individually. Rational for their use is provided, as well as the synthetic strategies investigated. Both platforms showed significant interference with the analysis assay, most pronounced for the adenine series. A primary goal throughout this thesis is the identification of a simple, rapid method to provide a library of new compounds. To this end, discussion of improved synthetic routes are provided within the section dedicated to guanines. Initial investigation into pterins as a platform for RTA inhibitors is provided in Chapter 3. Much of this chapter is concerned with hurtles encountered while dealing with the poor solubility of pterins, purification, and limits in reaction scope. Finally this chapter details a significant discovery in pterin's utility, both in terms of synthetic ease and preference towards one regioisomer over another. A variety of amides are initially used to probe the active site for significant interactions to the pterin pendents. Chapter 4 builds off the discoveries detailed within the previous chapter. Efforts to optimize the preliminary amide series from Chapter 3 are described, leading to a significant enhancement in activity. Additionally, Chapter 4 describes a synthetic breakthrough which greatly enhanced the speed of synthesis and complexity of the designed pterin inhibitors. Building upon the goal to map the RTA active site, a description of various peptide conjugated pterins is provided, as well as efforts to arrive at optimized isosteres of the most promising peptide derivatives.Chemistr

Design and Synthesis of a Potential Anti-fungal Agent

Fungal infections are a serious concern, as they impact many people and have high mortality rates for those who are immunocompromised. As a result of drug-resistant microbes, there is always a need for new drugs to combat these infections, without causing side effects in humans. Taking advantage of differences in the Methionine Synthase (MetSyn) enzyme, found in both humans and fungi, our desired antifungal drug class binds exclusively to the fungal enzyme, inhibiting growth while leaving the host unaffected. We are synthesizing, and improving the synthesis of, a variety of inhibitors using pterin and deazaguanine-based molecules as the folate mimic, an essential substrate for MetSyn function. We have been testing these molecules\u27 activity in a microbial growth assay

Synthesis of A. Mexicana Inspired Antimicrobial Agents

Bacterial and fungal infections occur when microorganisms invade the tissue and, if left untreated, can affect the whole body. Pathogenic bacterial and fungal infections are some of the leading causes of death in the population at large. Due to the ever-growing prevalence of drug-resistant “superbugs” and the lack of new antimicrobial drugs, there is a need to explore new and alternative pathways for fighting these diseases. Through a collaborative project, we have explored separation of key components of the seed, stem, leaves, and root of the Argemone mexicana plant to isolate antimicrobial agents found within this plant. We have already identified three key molecules which give this plant anti-microbial properties against gram-positive bacteria. We are now focused on designing and synthesizing new variants of these bioactive molecules in the hopes of discovering new, more potent, drugs

Mondialisation formation et développement dans les pays du Nord et du Sud

Dans un contexte de mondialisation, où l’économie, les évolutions politiques et socioculturelles jouent un rôle déterminant, les pratiques de formation des enseignants doivent être renouvelées pour répondre aux attentes de la société et en faisant une part importante à la professionnalisation.In the context of globalisation, in which the economy and political and socio-cultural changes play a major part, practises in teacher training must be renewed to respond to what society expects, insisting more particularly on professionalisation.En un contexto de mundialización, en el que la economia, las evolu-ciones politicas y socioculturales desempenan un papel determinante, las prâcticas de formación de los docentes deben renovarse para responder a las esperas de la sociedad otorgándole un lugar importante a la profesionalización

Progress Towards a Library of Potential Fungicides

Methionine Synthase (MetSyn) is an enzyme that uses folate and homocysteine to create the amino acid methionine, which is essential for all organisms. There are key differences between the fungal MetSyn enzyme and the mammalian (human) form, especially with regard to the proximity of the two binding sites for folate and homocysteine. Taking advantage of these differences, an antifungal drug could be developed to exclusively bind the fungal enzyme and inhibit fungal growth while leaving the host (patient) unaffected. We are currently exploring the synthesis of various molecules that mimic folate, an essential substrate for MetSyn function. We plan to screen these molecules against a multitude of fungal species as well as in an isolated system with the MetSyn enzyme itself

Progress Towards a Library of Potential Fungicides

Methionine Synthase (MetSyn) is an enzyme that uses folate and homocysteine to create the amino acid methionine, which is essential for all organisms. There are key differences between the fungal MetSyn enzyme and the mammalian (human) form, especially with regard to the proximity of the two binding sites for folate and homocysteine. Taking advantage of these differences, an antifungal drug could be developed to exclusively bind the fungal enzyme and inhibit fungal growth while leaving the host (patient) unaffected. We are currently exploring the synthesis of various molecules that mimic folate, an essential substrate for MetSyn function. We plan to screen these molecules against a multitude of fungal species as well as in an isolated system with the MetSyn enzyme itself

Elucidating the Antimicrobial Effects of \u3ci\u3eCurcuma longa\u3c/i\u3e, \u3ci\u3eCurcuma aerogunosia\u3c/i\u3e, and \u3ci\u3eZiginber officinale\u3c/i\u3e to Combat Superbugs Related to NASA Space Travel

According to recent studies, the International Space Station has been colonized by numerous bacteria and fungi, including several opportunistic pathogens that have been found to possess antimicrobial resistance. Despite this identified need, there has been a stark decrease in antimicrobial drug development in recent years, which has brought the isolation of novel antimicrobial agents to the forefront of modern healthcare. The increase of antimicrobial-resistant microorganisms, in addition to several scientific reports highlighting how space travel may place astronauts at a heightened risk of infection, has been a driving motivation to discover novel antimicrobial agents. Therefore, the research herein is focused on testing bacterial and fungal pathogens that have been isolated from the International Space Station against methanolic extracts from medicinal plants, such as Curcuma longa, Curcuma aerogunosia, and Ziginber officinale. Methanol extracts from bulbs vs. roots of C. longa, C. aerogunosia, and Z. officinale were separated and tested for antimicrobial activities with several specific extracts showing strong inhibitory effects against multiple bacterial and fungal lines. Further work is currently being conducted to identify the specific compounds responsible for this activity, as well as to better understand the potential mechanism of antimicrobial action. These data highlight the importance of plants as an invaluable pharmaceutical resource at a time when antimicrobial drug discovery has plateaued