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Student Number : 9906314R - MSc dissertation - School of Pathology - Faculty of Science / Inappropriate use of antimicrobial agents has been shown to select for organisms with resistance mechanisms (eg. efflux pumps), which could lead to the development of antibiotic resistance. The objective of this study was to investigate a possible link between antibiotic resistant gastrointestinal pathogens and reduced susceptibility to anti microbial agents found in commonly used household disinfectants. Tetracycline and ofloxacin resistant and sensitive Salmonella and E.coli species were isolated from fresh poultry and clinical samples. Ethidium bromide accumulation assays were performed to assess the presence of active efflux pumps. Using spectrophotometric accumulation assays, the extrusion of the active components of commercial household agents by the efflux pumps was tested. To determine changes in the efficacy of these products, in-use disinfectant testing was performed. Active efflux pumps and extrusion of the active ingredients was observed in the resistant but not in the sensitive organisms. When the household products were used at the recommended concentrations, a significant reduction of both resistant and sensitive bacteria was observed after the in-use disinfectant testing procedure. However, if the household products were used at concentrations below the recommended concentration, the resistant bacteria were not eliminated as efficiently as the sensitive bacteria.

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L’émergence des bactéries résistantes aux béta-lactamines et aux carbapénèmes, a abouti à la réintroduction de la colistine comme agent de dernier recours pour traiter les infections dues à ces germes. Cependant, les résistances chromosomique et plus récemment plasmidique à la colistine ont apparu. Ce problème de bactéries multi-résistantes a par la suite déclenché la publication d’articles alarmants sur les dangers de ces germes. Pour répondre à la dramatisation médiatique liée à ce problème, mon projet de thèse vise à proposer des stratégies thérapeutiques pour traiter les infections dues aux bactéries multi-résistantes. Dans un premier temps, nous avons testé l’activité d’un large panel comprenant des anciens antibiotiques contre les bactéries résistantes aux carbapénèmes et d’autres résistantes à la colistine. Plusieurs familles d’antibiotiques ont été efficaces contre ces 2 types de bactéries résistantes.Dans un deuxième temps, nous avons évalué l’activité d’antibiotiques combinés en vue de détecter une synergie d’action. Deux combinaisons synergiques ont été retenues : colistine + sulfadiazine et colistine + acide fusidique. Ces associations d’antibiotiques ont démontré un effet bactéricide sur une collection de bactéries Gram négatives résistantes à la colistine, et ceci indépendamment du mécanisme de résistance. / The emergence of beta-lactam and carbapenem resistant bacteria, resulted in the reintroduction of colistin as an agent of last resort to treat infections caused by these bacteria. However, chromosomal resistances and more recently plasmidic to colistin appeared. This problem of multidrug-resistant bacteria subsequently triggered the publication of alarming articles on the dangers of these germs. To answer the media dramatization related to this problem, my thesis project aims to propose therapeutic strategies to treat infections due to multiresistant bacteria.Initially, we tested the activity of a large panel including old antibiotics against carbapenem resistant bacteria and others resistant to colistin. Several families of antibiotics have been effective against these two types of resistant bacteria.In a second step, we evaluated the activity of combined antibiotics in order to detect a synergistic action. Two synergistic combinations were retained: colistin + sulfadiazine and colistin + fusidic acid. These combinations of antibiotics have shown a bactericidal effect on a collection of Gram-negative colistin-resistant bacteria, independent of the resistance mechanism.

This thesis describes the development of new pathways towards the synthesis of novel antimicrobial (and anticancer) agents. Two synthetic protocols based on free radical chemistry are studied, which are used to access polycyclic heterocyclic compounds of potential biological importance. Both these procedures involve the generation of radicals using Bu3SnH and AIBN initiators, and the subsequent intramolecular radical cyclisation onto the imidazole ring. Radical cyclisations onto benzimidazoles and pyrroles are also described.

Lentinula edodes é um cogumelo comestível que possui qualidades nutricionais, terapêuticas e medicinais. Além disso, muitos estudos na área médica têm comprovado que o cogumelo possui efeito antibiótico sobre microrganismos patogênicos ao homem. Na área agrícola, alguns trabalhos realizados com o cogumelo demonstraram possíveis efeitos no controle de fitopatógenos. O presente trabalho teve como objetivo demonstrar a produção de substâncias antimicrobianas por L. edodes ativas sobre Colletotrichum sublineolum, agente causal da antracnose em sorgo, Alternaria solani, responsável pela pinta preta do tomateiro, Xanthomonas axonopodis pv. passiflorae, agente causal da mancha bacteriana em maracujazeiro e Tobacco mosaic virus (TMV), causador de mosaico foliar em fumo. Para os testes com C. sublineolum e A. solani foram utilizados extratos aquosos de L. edodes, obtidos a partir de basidiocarpos desidratados em pó, dos isolados LE JAB-K, LE 96/22, LE 96/17 e LE 95/01. Os resultados evidenciaram que o extrato aquoso de basidiocarpos do isolado LE 96/22 inibiu o crescimento micelial in vitro e a formação de apressórios por C. sublineolum. Já os extratos dos isolados LE JAB-K e LE 95/01 apresentaram efeito inibitório na germinação de conídios e na formação de apressórios do patógeno. Em contrapartida, os extratos aquosos de basidiocarpos dos diferentes isolados de L. edodes não apresentaram efeito inibitório na germinação dos conídios e no crescimento micelial de A. solani. Por sua vez, os extratos aquosos de basidiocarpos a 20% (v/v) e o filtrado do crescimento micelial de L. edodes, misturados à suspensão de X. axonopodis pv. passiflorae, exibiram redução na multiplicação bacteriana. Todos os extratos aquosos de basidiocarpos dos diferentes isolados testados na multiplicação da bactéria mostraram-se termolábeis, quando autoclavados a 121 °C por 20 min. Em experimentos com plantas de fumo, os extratos aquosos de basidiocarpos dos isolados LE 96/17 e LE 96/22 adicionados à suspensão contendo partículas do TMV reduziram significativamente a ocorrência de lesões locais nas folhas. O extrato aquoso do isolado LE 96/22 apresentou compostos antivirais de natureza termoestável. Finalmente, o extrato aquoso de basidiocarpos do isolado LE 96/22, o qual apresentou a maior atividade antimicrobiana, foi purificado parcialmente por cromatografia de troca aniônica (CTA). O pico V apresentou efeito inibitório no crescimento micelial de C. sublineolum. Por sua vez, a multiplicação de X. axonopodis pv. passiflorae foi inibida pelos picos IV, V e VII. Já os picos I, II e III, obtidos em CTA por gradiente linear de NaCl e o pico I obtido em CTA pelo método "step wise", reduziram significativamente a infectividade do TMV em plantas de fumo. Com base nesses resultados, evidencia-se a ação de preparações de L. edodes sobre fitopatógenos, o que demonstra o uso potencial do mesmo no controle de agentes causais de doenças infecciosas em plantas. / Lentinula edodes is an edible mushroom that has nutritious, therapeutical and medicinal qualities. Moreover, many studies in the medical area have shown that the mushroom exhibits antibiotic effects on pathogenic microorganism to the man. In the agricultural area, work carried out with the mushroom has demonstrated its possible effects to control phytopathogens. The objective of the present work was to demonstrate the productionof antimicrobial substances of L. edodes active on Colletotrichum sublineolum, causal agent of anthracnose in sorghum, Alternaria solani, responsible for the black spot of the tomato plants, X. axonopodis pv. passiflorae, causal agent of the bacterial spot in passion fruit plants and on Tobacco mosaic virus, causal agent of the mosaic in tobacco plants. For the test with C. sublineolum and A. solani aqueous extracts were obtained from dehydrated fruiting bodies from the shiitake isolates LE JAB-K, LE 96/22, LE 96/17 and LE 95/01. The results showed that the fruiting body aqueous extract from isolate LE 96/22 inhibited micelial growth and appressorium formation by C. sublineolum. The aqueous extracts of isolates LE JAB-K and LE 95/01 exhibited inhibitory effect on conidium germination and on formation of appressorium by the patogen. On the other hand, the extracts of the different isolates of L. edodes did not exhibit inhibitory effect on conidium germination and micelial growth of A. solani. The aqueous extracts of fruiting bodies at 20% (v/v) concentration and filtrate of the micelial growth of L. edodes, when mixed to the suspension of X. axonopodis pv. passiflorae, exhibited decreased on bacterial multiplication. All the aqueous extracts of fruiting bodies tested from the different isolates in the bacterial multiplication were thermobile, when heated at 121 °C for 20 min. In experiments with tobacco plants, the aqueous extracts of fruiting bodies of isolates LE 96/17 and LE 96/22 when added to the suspension of TMV reduced the amount of local lesions on the leaves. When the aqueous extracts of LE 96/22 were heated the antiviral nature was not lost. Finally, the aqueous extract of fruiting bodies from isolate LE 96/22 that presented major antimicrobial activity was partially purified by anion exchange chromatography (AEC). The peak V exhibited inhibitory effect on micelial growth of C. sublineolum. Multiplication of X. axonopodis pv. passiflorae was inhibited by peaks IV, V and VII. Regarding TMV infectivity, peaks I, II and III, obtained in CTA through linear gradient of NaCl, and peak I also obtained through CTA by the method "step wise", significantly reduced virus infectivity in tobacco plants. Based upon these results, it is shown that preparations of L. edodes can interfere whith phytopathogen multiplication, demonstrating its potential to control plant diseases.

Peptidomimetics can mimic hierarchical structures of peptides and proteins. Thus, they are extensively studied for therapeutic applications. To break the limitation of backbones and frameworks and expand the peptidomimetics family, a new class of peptidomimetics - “γ-AApeptides” was developed. Design of γ-AApeptides is based on the chiral peptide nucleic acids (PNAs) backbone. The World Health Organization estimates that one -third of all deaths in the world are on account of infectious diseases. AMPs are important because of their high activity against broad spectrum microbes, less susceptible to grow resistance and selectivity in binding to bacterial cells over human cells. γ-AApeptides as a new class of peptidomimetics have increased stability and enhanced chemical diversity. We have developed polymyxin mimic cyclic peptides, small linear molecules and hydantoin derivatives as potent antibiotic agents with γ-AApeptides. They have good bioactivity and selectivity. Combinatorial library is key technology for accelerating the discovery of novel therapeutic agents. One-bead-two-compound γ-AApeptides-based library was developed and screened against SMYD2 protein which is essential for tumor growing.