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Melanoma é o câncer mais agressivo e a mutação BRAF V600E é a mais frequente entre os pacientes. O vemurafenibe foi o primeiro inibidor específico desta mutação aprovado pela Food and Drug Administration. Entretanto, após cerca de seis meses há recidiva e superar os mecanismos de resistência responsáveis por este fenômeno ainda é um desafio. A curcumina é um tumérico com características antitumorais e anti-inflamatórias, entretanto sua baixa biodisponibilidade e estabilidade limitam seu uso e por isso impulsionaram a busca por análogos capazes de serem eficientes e comercializados. O DM-1, é um análogo monocetônico que apresentou efeitos antiumorais in vitro e in vivo em estudos anteriores. O objetivo deste trabalho foi avaliar os efeitos citotóxicos do DM-1 em células de melanoma sensíveis (naive) e resistentes ao vemurafenibe, bem como na modulação de metaloproteinases. As células de melanoma foram tratadas com diferentes concentrações de DM-1, e este composto foi citotóxico para linhagens sensíveis e resistentes ao vemurafenibe, além de induzir parada de ciclo celular em G1/G0 e diminuir o número de colônias, entretanto ele não foi seletivo em ensaios de citotoxicidade realizados com melanócitos e fibroblastos. O tratamento dessas células em doses subtóxicas resultou na modulação de metaloproteinases importantes no processo de invasão celular. O DM-1 reduziu as concentrações das metaloproteinases -1, -2 e -9 (MMP-1, -2 e -9) em um ensaio de quantificação de MMPs e a atividade das MMP-2 e -9 em um ensaio de zimografia de maneira célula dependente. As modulações negativas do inibidor de MMP TIMP-2 e MMP-14 para SKMEL-28 naive foram associadas a diminuição das atividades de MMP-2 e -9, enquanto que as modulações positivas para SKMEL-19 naive foram relacionadas ao aumento de MMP-2. Este composto ainda inibiu a migração das células e a formação de tubos por células endoteliais. / Malignant melanoma is the most aggressive cancer and the BRAF V600E mutation is the most frequent among patients. Vemurafenib was the first specific inhibitor for this mutation approved by Food and Drug Administration. Therefore around six months later there is relapse and overcoming it is still a challenge. Curcumin is a turmeric and it has been deeply researched because of its anti-inflammatory and antitumoral effects. However the low stability limits its use, therefore, encouraged the investigation of analogues capable to be efficient and commercialized. DM-1 is a monoketone curcumin analog and it showed antitumoral effects in vitro and in vivo in previous studies The aim of this project was to evaluate the cytotoxical effects of DM-1 for vemurafenib responsive (naïve) and resistant melanoma cells, as well as metalloproteinases modulation. Melanoma cells were treated with different DM-1 concentrations, and this compound was cytotoxic for responsive and resistant cell lines, besides inducing G1/G0 cell cycle arrest and reducing the number of colonies, nonetheless it was not selective in assays performed with melanocytes and fibroblasts. Subtoxic treatment of those cells modulated important MMPs in the cell invasion process. DM-1 reduced metalloproteinases -1, -2 and -9 (MMP-1,-2 and -9) in a quantification assay, and MMP-2 and -9 activities by zymography in a cell-dependent way. Negative modulations of MMP inhibitor TIMP-2 and MMP-14 for SKMEL-28 naïve were associated with MMP-2 and -9 reduced activities, whereas positive modulations for SKMEL-19 naïve were correlated to MMP-2 increase. Furthermore, this compound reduced migration of those cells and endothelial cell tube formation.

Biosynthetic natural products are invaluable resources that have been gleaned from the environment for generations, and they play an essential role in drug development. Natural product biosynthesis also possesses the latent ability to affect biological systems adversely. This work implements recent advances in genomic, proteomic and microbiological technologies to understand further biosynthetic molecules that may influence progression of human disease. Azinomycin A and B are antitumor metabolites isolated from the terrestrial bacterium Streptomyces sahachiroi. The azinomycins possess an unusual aziridine [1,2-a] pyrrolidine ring that reacts in concert with an epoxide moiety to produce DNA interstrand cross-links. Genomic sequencing of S. sahachiroi revealed a putative azinomycin resistance protein (AziR). Overexpression of AziR in heterologous hosts demonstrated the protein increases cell viability and decreases DNA damage response in the presence of azinomycin. Fluorescence titration indicated AziR functions as an azinomycin binding protein. An understanding of azinomycin resistance is important for future engineering and drug delivery strategies. Additionally, the S. sahachiroi draft genome obtained via 454 pyrosequencing and Illumina sequencing revealed several silent secondary metabolic pathways that may provide new natural products with biomedical application. β-lactoglobulin (BLG), the most abundant whey protein in bovine milk, has been observed to promote the self-condensation of retinal and similar α,β-unsaturated aldehydes. BLG is a possible non-genetic instigator of cycloretinal and A2E accumulation in the macula, a condition associated with age-related macular degeneration. BLG-mediated terpenal condensation has been optimized for in vitro study with the retinal mimic citral. In rabbits fed retinal and BLG or skim milk, cycloretinal formation was detected in the blood by 1H-NMR, and SDS-PAGE analysis indicated BLG was present in blood serum, suggesting the protein survives ingestion and retains catalytic activity. Mass spectrometry and site-directed mutagenesis provided mechanistic insight toward this unusual moonlighting behavior. The experiments described in this dissertation serve to further natural product biosynthesis discovery and elucidation as they relate to consequences for human health. Efforts to solve azinomycin biosynthesis via enzymatic reconstitution, characterize compounds produced by orphan gene clusters within S. sahachiroi, and obtain a clear mechanism for BLG-promoted cycloterpenal formation are immediate goals within the respective projects.

Melanoma é o câncer mais agressivo e a mutação BRAF V600E é a mais frequente entre os pacientes. O vemurafenibe foi o primeiro inibidor específico desta mutação aprovado pela Food and Drug Administration. Entretanto, após cerca de seis meses há recidiva e superar os mecanismos de resistência responsáveis por este fenômeno ainda é um desafio. A curcumina é um tumérico com características antitumorais e anti-inflamatórias, entretanto sua baixa biodisponibilidade e estabilidade limitam seu uso e por isso impulsionaram a busca por análogos capazes de serem eficientes e comercializados. O DM-1, é um análogo monocetônico que apresentou efeitos antiumorais in vitro e in vivo em estudos anteriores. O objetivo deste trabalho foi avaliar os efeitos citotóxicos do DM-1 em células de melanoma sensíveis (naive) e resistentes ao vemurafenibe, bem como na modulação de metaloproteinases. As células de melanoma foram tratadas com diferentes concentrações de DM-1, e este composto foi citotóxico para linhagens sensíveis e resistentes ao vemurafenibe, além de induzir parada de ciclo celular em G1/G0 e diminuir o número de colônias, entretanto ele não foi seletivo em ensaios de citotoxicidade realizados com melanócitos e fibroblastos. O tratamento dessas células em doses subtóxicas resultou na modulação de metaloproteinases importantes no processo de invasão celular. O DM-1 reduziu as concentrações das metaloproteinases -1, -2 e -9 (MMP-1, -2 e -9) em um ensaio de quantificação de MMPs e a atividade das MMP-2 e -9 em um ensaio de zimografia de maneira célula dependente. As modulações negativas do inibidor de MMP TIMP-2 e MMP-14 para SKMEL-28 naive foram associadas a diminuição das atividades de MMP-2 e -9, enquanto que as modulações positivas para SKMEL-19 naive foram relacionadas ao aumento de MMP-2. Este composto ainda inibiu a migração das células e a formação de tubos por células endoteliais. / Malignant melanoma is the most aggressive cancer and the BRAF V600E mutation is the most frequent among patients. Vemurafenib was the first specific inhibitor for this mutation approved by Food and Drug Administration. Therefore around six months later there is relapse and overcoming it is still a challenge. Curcumin is a turmeric and it has been deeply researched because of its anti-inflammatory and antitumoral effects. However the low stability limits its use, therefore, encouraged the investigation of analogues capable to be efficient and commercialized. DM-1 is a monoketone curcumin analog and it showed antitumoral effects in vitro and in vivo in previous studies The aim of this project was to evaluate the cytotoxical effects of DM-1 for vemurafenib responsive (naïve) and resistant melanoma cells, as well as metalloproteinases modulation. Melanoma cells were treated with different DM-1 concentrations, and this compound was cytotoxic for responsive and resistant cell lines, besides inducing G1/G0 cell cycle arrest and reducing the number of colonies, nonetheless it was not selective in assays performed with melanocytes and fibroblasts. Subtoxic treatment of those cells modulated important MMPs in the cell invasion process. DM-1 reduced metalloproteinases -1, -2 and -9 (MMP-1,-2 and -9) in a quantification assay, and MMP-2 and -9 activities by zymography in a cell-dependent way. Negative modulations of MMP inhibitor TIMP-2 and MMP-14 for SKMEL-28 naïve were associated with MMP-2 and -9 reduced activities, whereas positive modulations for SKMEL-19 naïve were correlated to MMP-2 increase. Furthermore, this compound reduced migration of those cells and endothelial cell tube formation.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21958号 / 医博第4500号 / 新制||医||1037(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中川 一路, 教授 松原 和夫, 教授 西渕 光昭 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

L’émergence de bactéries multirésistantes aux antibiotiques conduit la médecine humaine et vétérinaire à des impasses thérapeutiques. L’usage abusif des ATBs accélère et accentue fortement le processus d’antibiorésistance. Le but de mon travail de thèse était d’apporter une solution au problème de surconsommation d’ATBs en médecine vétérinaire, particulièrement dans les élevages, tout en garantissant la santé animale. Nous avons développé une approche de thérapie combinatoire basée sur l’association d’ATBs déjà existants avec des molécules adjuvantes. Nous avons ainsi évalué l’activité de différents dérivés polyaminés d’origine naturelle sur des pathogènes dits « ESKAPE » qui présentent une relevance clinique majeure en médecine humaine. Ces différentes études ont permis de développer des protocoles de criblage, mais également des méthodes permettant d’élucider leur impact sur la physiologie bactérienne.Nous avons testé l’activité de ces composés en combinaison avec le florfénicol, ATB couramment utilisé pour traiter les infections respiratoires chez le porc. Après avoir identifié un adjuvant au florfénicol, nous avons pu déterminer son mode d’action par différentes méthodes de fluorescence et de bioluminescence. Nous avons pu démontrer que le composé permet de potentialiser l’activité de l’ATB par une action membranotrope et par une inhibition de l'efflux, augmentant ainsi la concentration intracellulaire en ATB, mais également par une inhibition de la force proton motrice (FPM). La motricité flagellaire des bactéries, est un facteur de virulence fonctionnant avec la FPM nous avons pu mettre en évidence une inhibition de la mobilité par le composé. / The constant increase of multidrug resistant bacteria is leaving clinicians and veterinarians with very limited options to treat bacterial infections. The main goal of my work was find a chemical solution to reduce the use of antibiotics in veterinary medicine, especially in swines, without affecting the health of the livestock. To achieve this goal, we have developed a drug combination approach based on the association of antibiotics with chemosensitizers, herein called adjuvants, some of which were polyamines derivatives from natural sources. To provide the proof of concept, combination of several derivatives from different chemical sources (marine sponges and plants) have been tested ex vivo on « ESKAPE » pathogens, which are among the most urgent bacterial threats. Results from these studies allowed us to develop procedures for screening antibacterial activities and methodologies for understanding the impact of the selected adjuvants on bacterial physiology.Florfenicol is a widely used antibiotic to treat respiratory infections in swine. Therefore, derivatives were further assessed in combination with florfenicol, and florfenicol adjuvants were identified. The mode of action of one chosen adjuvant on bacterial membranes was further investigated by using fluorescence and bioluminescence methods. Data showed that this molecule was able to potentiate the antibiotic activity by increasing its intracellular concentration (membranotrope activity and inhibition of efflux) but also causes inner membrane depolarization. Flagellar motility represents an important virulence factor which use PMF, and we showed a diminution of the motility's halo with our compound.

Antibiotic resistance in multidrug resistant bacteria cause high mortality rates worldwide, where there has been over 1,000,000 deaths reported as of the year 2019. Antibiotics were thought to be the cure for fighting infectious diseases and preventing further spreading of infection. This became a major problem due to bacteria evolving and developing mechanisms for resistance. The purpose of this review was to see if there are differences in the resistance mechanism of gram negative and gram positive bacteria, focusing mainly on the six most common multidrug resistant pathogenic bacteria; Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecium, Acinetobacter baumannii, Klebsiella pneumoniae and Streptococcus pneumoniae. The results show that there is a difference in the resistance mechanism between gram positive and gram negative multidrug resistant bacteria. The difference in resistant mechanisms is due to the cell wall compositions of gram negative and gram positive bacteria. The main difference as to why the gram negative bacteria have more resistance is due to the outer membrane. Antibiotics have a hard time to diffuse through and into the cell, that is they can easily decrease their outer membrane permeability. Gram positive bacteria lack an outer membrane which makes them become more susceptible to antibiotics. The most common antibiotic resistance mechanisms in gram negative bacteria are outer membrane mechanisms such as lipid A and lipopolysaccharide modification as well as mutations in porin channels. On the other hand, the most common resistance mechanisms for gram positive bacteria are point mutations especially in penicillin binding proteins as well mutations in the rpoB gene. One important gram positive bacteria is Methicillin resistant Staphylococcus aureus, which developed a new mechanism against antibiotics, a missense mutation and mutation on the promoter region in penicillin binding protein 4. Recently new research has come forward showing that N-chlorotaurine (NCT) inhibits resistance in both gram positive and gram negative multidrug resistant bacteria. The research on NCT is still fairly new and only time will tell if this method of inhibiting resistance will be used in the future. This review highlights the importance and concern of multidrug resistance bacteria, especially due to bacteria being able to rapidly evolve when antibiotics are used incorrectly. It is important to understand the differences in resistance between gram negative and gram positive bacteria and how resistance spreads. This knowledge can be used to develop antibiotics that treat infections. It is however still a challenge to overcome resistance in multidrug resistant bacteria due to evolutionary adaptation especially through horizontal gene transfer, where resistant bacteria can adapt to changing conditions. / Antibiotikaresistens hos multiresistenta gramnegativa och grampositiva bakterier orsakar hög dödlighet över hela världen, där det har rapporterats över 1,000,000 dödsfall för år 2019. Antibiotika ansågs vara botemedlet för att bekämpa infektionssjukdomar och förhindra ytterligare spridning av infektioner. Detta blev ett stort problem på grund av att bakterier utvecklades mekanismer för resistens, vilket gör att de kan överleva när de behandlas med antibiotika. Syftet med denna studien är att se om det finns skillnader i resistensmekanismener för gramnegativa och grampositiva bakterier, med fokus på de sex vanligaste multiresistenta bakterierna; Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecium, Acinetobacter baumannii, Klebsiella pneumoniae och Streptococcus pneumoniae. Resultaten visar att det finns en skillnad i resistensmekanismen mellan grampositiva och gramnegativa multiresistenta bakterier. Skillnaden i resistenta mekanismer beror på cellväggssammansättningen av gramnegativa och grampositiva bakterier. Den största skillnaden till varför de gramnegativa bakterierna har mer resistens beror på det yttre membranet. Antibiotika har svårt att penetrera genom och in i cellen genom att minska deras yttre membranpermeabilitet. Grampositiva bakterier saknar ett yttre membran som gör att de blir mer mottagliga för antibiotika. De vanligaste antibiotikaresistensmekanismerna hos gramnegativa bakterier är yttre membranmekanismer som lipid A och lipopolysackaridmodifiering samt mutationer i porinkanaler. De vanligaste resistensmekanismerna för grampositiva bakterier är punktmutationer, särskilt i penicillinbindande proteiner samt mutationer i rpoB genen. En viktig grampositiv bakterie är Meticillin-resistent Staphylococcus aureus, som utvecklade en ny mekanism mot antibiotika, en missense-mutation och mutation på promotorregionen i penicillinbindande protein 4. Nyligen har ny forskning kommit fram som visar att N-klorotaurin (NCT) hämmar resistens i både grampositiva och gramnegativa multiresistenta bakterier. Forskningen om NCT är fortfarande ny och bara tiden kommer att utvisa om denna metod för att hämma resistens kommer att användas i framtiden. Den här studien belyser vikten och oron för multidresistena bakterier, särskilt på grund av att bakterier snabbt kan utveckla antibiotikaresistens när antibiotika används på fel sätt. Det är viktigt att förstå skillnaderna i resistens mellan gramnegativa och grampositiva bakterier och hur resistens sprids inom resistenta bakterier. Denna kunskap kan användas för att utveckla antibiotika som behandlar infektioner orsakade av både gramnegativa och grampositiva bakterier. Det är fortfarande en utmaning att övervinna resistens hos multiresistenta bakterier på grund av evolutionär anpassning särskilt genom horisontell genöverföring, där resistenta bakterier kan anpassa sig till förändrande förhållanden.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Antimicrobial resistance is considered a serious public health problem worldwide and complicates the treatment of infections caused by resistant microorganisms. The carbapenems are antimicrobial agents considered the last resource for treatment of severe infections caused by Klebsiella pneumoniae and the resistance to β-lactams can result in the accumulation of different resistance mechanisms (carbapenemases, efflux pump and loss of porins). This study aimed to evaluate multiple resistance mechanisms in 27 clinical isolates of K. pneumoniae resistant to carbapenems coming from the University Hospital of Santa Maria-RS from July 2013 to August 2014. These isolates were evaluated the susceptibility profiles through broth microdilution against ciprofloxacin, imipenem, ertapenem, meropenem, cefepime, ceftazidime and cefoxitin. Carbapenemase detection was performed through phenotypic tests with combined disc test with phenylboronic acid (AFB) and ethylenediaminetetraacetic acid (EDTA) and Blue-Carba test. In addition, genotypic tests to detect genes enconding carbapenemase were performed. Efflux pump was evaluated by broth microdilution together with efflux pump inhibitor and loss of porins were evaluated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). High levels of resistance verified by the minimum inhibitory concentration (MIC) 50 and 90 for ciprofloxacin (64 and 128μg/mL), imipenem (32 to >128μg/mL), ertapenem (>128 and >128μg/mL), meropenem (128 and >128 μg/mL), cefepime (>128 and >128 μg/mL), ceftazidime (64 and 128μg/mL) and cefoxitin (128 and >128 μg/mL), respectively. In the resistance through carbapenemases production, 89% of the clinical isolates showed blaKPC gene and no clinical isolated showed genes encoding the metallo- β-lactamases. It was observed that the Blue-Carba test and combined disc test with AFB showed 100% concordance, while the combined disc test with EDTA showed high number of false positive (48%) when compared with genotypic test. Four isolates showed phenotypic profile consistent with the presence of efflux pump and all clinical isolates had lost one or both porins, being that in three isolated, this was the only resistance mechanism found. In 14% of the isolates can observe simultaneously observe the presence of three resistance mechanisms. Consequently, it is of fundamental scientific interest that studies are conducted in order to investigate and understand the mechanisms involved in resistance to carbapenems in order to assist strategies of prevention and infection control. / A resistência aos antimicrobianos é considerada um grave problema de saúde pública em âmbito mundial e dificulta o tratamento de infecções causadas por microrganismos resistentes. Os carbapenêmicos são os antibacterianos considerados último recurso para o tratamento de infecções graves causadas por Klebsiella pneumoniae e a resistência a esse grupo de β-lactâmicos pode resultar da acumulação de diferentes mecanismos de resistência (carbapenemases, bomba de efluxo e perdas de porinas). Este trabalho teve como objetivo avaliar os múltiplos mecanismos de resistência de 27 isolados clínicos de K. pneumoniae resistente a carbapenêmicos oriundos do Hospital Universitário de Santa Maria-RS no período de julho de 2013 a agosto de 2014. Foram avaliados os perfis de suscetibilidade desses isolados através de microdiluição em caldo frente aos antimicrobianos ciprofloxacino, imipenem, ertapenem, meropenem, cefepima, ceftazidima e cefoxetina. A detecção de carbapenemases foi realizada através de testes fenotípicos com a utilização do disco de antimicrobiano associado com os inibidores ácido fenilborônico (AFB) e ácido etilenodiamino tetra-acético (EDTA) e através do teste Blue-Carba. Também foram realizados testes genotípicos para detectar os genes que codificam as carbapenemases. Bombas de efluxo foram avaliadas através de microdiluição em caldo juntamente com inibidor de bomba de efluxo e a perda de porinas foi avaliada pela eletroforese em gel de sulfato de dodecilo de sódio-poliacrilamida (SDS-PAGE). Altos níveis de resistência foram verificados nesses isolados pela concentração inibitória mínima (CIM) 50 e 90 para ciprofloxacino (64 e 128μg/mL), imipenem (32 e >128μg/mL), ertapenem (>128 e >128μg/mL), meropenem (128 e >128 μg/mL), cefepima (>128 e >128μg/mL), ceftazidima (64 e 128μg/mL) e cefoxitina (128 e >128 μg/mL), respectivamente. Na resistência através da produção de carbapenemases, 89% dos isolados apresentaram o gene blaKPC e nenhum isolado apresentou genes que codificam as metalo-β-lactamases. Foi observado que os testes Blue-Carba e disco combinado com AFB apresentaram 100% de concordância, enquanto o teste de disco combinado com EDTA apresentou elevado número de falso-positivos (48%) quando comparados com o teste genotípico. Quatro isolados apresentaram perfil fenotípico compatível com a presença de bomba de efluxo e todos os isolados apresentaram perda de uma ou ambas porinas, sendo que em três isolados, esse foi o único mecanismo de resistência encontrado. Em 14% dos isolados pode-se observar concomitantemente a presença dos três mecanismos de resistência. Devido ao exposto, é de fundamental interesse científico que estudos sejam realizados para investigar e compreender os mecanismos envolvidos na resistência aos carbapenêmicos, a fim de auxiliar em estratégias de prevenção e controle de infecção.

Seit 1998 ist erstmals eine gegen Heterodera schachtii resistente Zuckerrübensorte in Deutschland zugelassen. Diese wurde in einem dreijährigen Versuchsprogramm (1998-2000) an vier Standorten in unterschiedlichen Regionen Deutschlands angebaut, um methodische Fragen sowie die Auswirkung auf die Nematodenpopulation zu untersuchen. Unter Nematodenbefall reagierte die resistente Zuckerrübe mit einer konstanten Ertragsleistung, war also tolerant. Auf den vier Standorten kam es unter der resistenten Sorte zu keiner bzw. nur geringer Nematodenvermehrung.Die Resistenz der Sorte wurde im Biotest anhand der Transmissionsrate beurteilt. Auf 92-95 % der Pflanzen aus der Versuchssorte wurde das Resistenzgen übertragen, lediglich ein geringer Anteil von 5-8 % war anfällig. In Feldversuchen wurden die unter kontrollierten Bedingungen ermittelten Übertragungsraten nur teilweise bestätigt; zufällig bedingte Varianzen waren möglicherweise die Ursache.Um abgesicherte Aussagen über das Resistenz- und Toleranzniveau der Versuchssorte zu erhalten, muss ein Mindestaufwand bei den Untersuchungen eingehalten werden (Mischprobe aus 40 Bodeneinstichen je Parzelle von ca. 10 m2 Größe, davon ist ca. 1,8 kg Boden zu untersuchen). Auf dieser Basis können das Ertragsniveau der Sorte und ihre Auswirkung auf die Nematodenpopulation mit Hilfe von Regressionskurven beschrieben werden. Wenn dieser Aufwand aus ökonomischen Gründen nicht möglich ist, erscheint eine Reduzierung auf 900 g Boden noch vertretbar, führt allerdings zu verringerter Aussagesicherheit.Die Resistenz hatte keinen Einfluss auf die Anzahl der in die Wurzeln ein- bzw. ausgewanderten Larven. An den resistenten Zuckerrüben entwickelten sich mehrheitlich Männchen aber kaum Weibchen. Der Resistenzmechanismus beeinflusst also die geschlechtliche Entwicklung des Nematoden. Allerdings war eine erhöhte Männchenanzahl an resistenten Zuckerrüben nicht nachweisbar. Der Resistenzmechanismus führt wahrscheinlich zu einer frühzeitigen Stagnation weiblicher Larven. Der Einfluss eines mehrmaligen Anbaus einer resistenten Sorte auf das Potenzial pilzlicher Nematodenantagonisten im Boden wurde bei fünfmaligem Anbau der Sorte auf demselben Boden untersucht (zweimal Beprobung aus Feld- und dreimal aus Gewächshausanbau). Dabei lag die Parasitierungsrate der Nematodeneier in Feldböden bei der resistenten Sorte deutlich niedriger als bei anfälligen Zuckerrüben. Diese Beeinträchtigung pilzlicher Eiparasiten hat lediglich einen vorübergehenden Charakter, da die Raten nach erneutem Anbau anfälliger Pflanzen wieder ansteigen. Die absolute Anzahl parasitierter Eier und Larven war mit der Populationsdichte des Nematoden positiv korreliert; vermutlich werden pilzliche Eiparasiten durch ein erhöhtes Nahrungsangebot gefördert.