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Antitubulin Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The epothilones were originally identified as metabolites produced by the soil-dwelling myxobacterium Sorangium cellulosum So ce90 strain (Figure 4.21) obtained from a soil sample collected from the banks of the Zambesi River in South Africa, as part of a screening program for myxobacteria metabolites carried out by researchers from the Gesellschaft fur Biotechnologische Forschung (GBF) Institute in 1985. The structure of epothilone A was determined in 1996 using X-ray crystallography, and by 2008, epothilones B to F had been identified and characterized (see Figure 4.20). Early studies in tumor cell lines suggested superior potency compared to the taxanes, and this paved the way for preclinical studies and the potential development of epothilone analogs as anticancer agents. This research and development was led by Bristol-Myers Squibb (BMS), who had previous experience with developing paclitaxel. BMS commercialized the first example of an epothilone, ixabepilone (IxempraTM) (Figure 4.24), which received approval by the FDA in 2007 for the treatment of metastatic breast cancer.
Proteomics Approaches to Uncover the Drug Resistance Mechanisms of Microbial Biofilms
Published in Chaminda Jayampath Seneviratne, Microbial Biofilms, 2017
Chaminda Jayampath Seneviratne, Tanujaa Suriyanarayanan, Lin Qingsong, Juan Antonio Vizcaíno
Another proteomics study has been performed on the biofilms of susceptible and resistant A. hydrophila strains that were subjected to chlortetracycline treatment to induce stress [18]. The analysis identified an increase of fatty acid biosynthesis proteins in the resistant strains. The study demonstrated that increase in fatty acid biosynthesis may play an important role in antibiotic resistance of A. hydrophila. Hence the study suggested that a cocktail of chlortetracycline and triclosan may be a more effective therapy for A. hydrophila biofilm infections. A proteomics study was performed on the inhibitory effects of carolacton, a secondary metabolite isolated from the myxobacterium Sorangium cellulosum, exhibiting strong destructive effects on S. mutans biofilms using a 2-DE gel-based approach [73]. In this study, the proteome profile of drug-treated planktonic versus untreated planktonic S. mutans and drug-treated biofilm versus untreated biofilm S. mutans were compared. Proteins from the cytoplasmic and extracellular fractions of S. mutans were analysed, with a total of 239 protein spots, of which 192 were cytoplasmic proteins. The study demonstrated that in both planktonic and biofilm cells, the inhibitory effects of carolacton were exerted by disturbing peptidoglycan biosynthesis and degradation. This suggested that damage to cell wall integrity leads to cell death on treatment with carolacton.
Enhanced anti-proliferative efficacy of epothilone B loaded with Escherichia coli Nissle 1917 bacterial ghosts on the HeLa cells by mitochondrial pathway of apoptosis
Published in Drug Development and Industrial Pharmacy, 2018
Wenxing Zhu, Lujiang Hao, Xinli Liu, Orlando Borrás-Hidalgo, Yuyu Zhang
The epothilones produced by the myxobacterium Sorangium cellulosum constitute a new class of highly promising anti-cancer agents [1,2]. These agents belong to a 16-member family with ring macrolides combined with a methylthiazole side chain [3]. Epothilones bind to β-tubulin subunit of the αβ-tubulin dimer of microtubules, stabilize preformed microtubules and lead to aberrant spindle formation during mitosis with subsequent mitotic arrest and cell apoptosis [4,5]. The anti-cancer mechanism of epothilones was similar to paclitaxel, while the epothilones have better efficacy on paclitaxel-susceptible and paclitaxel-resistant cancer cells that display a multidrug-resistance phenotype due to overexpression of the P-glycoprotein (P-gp) efflux pump [6,7]. Epothilones, especially epothilone B (Epo B) and its derivatives, were shown to induce regression of various types of human cancers including glioma, colon, breast, lung, and ovarian carcinomas [8]. However, the systemic application of epothilones causes some toxic side effects, such as neutropenia, sensory neuropathy, diarrhea, nausea, fatigue, and vomiting [9,10]. In order to overcome or reduce these undesired effects and maintaining the drug potency, epothilones might be encapsulated into drug delivery vehicles to allow a site-specific targeting and prolong the drugs circulation time inside the body.
Boron’s neurophysiological effects and tumoricidal activity on glioblastoma cells with implications for clinical treatment
Published in International Journal of Neuroscience, 2019
Meric A. Altinoz, Gulacti Topcu, İlhan Elmaci
The chemistry of boron is determined by its feature to develop trigonal and tetrahedral complexes with hydroxyl groups [7]. Organoboranes in biological systems interact with hydroxyl and amine groups [2]. Boron has a high affinity for oxygen to form borates with enzyme inhibitory efficacies and the physicochemical features of boronic acids render these compounds as versatile candidates for drug development. Boron atoms in biological systems interact with proteins via strong hydrogen bonds and weaker covalent bonds, which provide biological effects (i.e. antiparasitic, antifungal, protease inhibitors and others) [2]. Boron compounds were employed for thousands of years including human mummification in Egypt [10]; and the first recorded medicinal use of boron was by Arabian physicians in 875 AD [8]. This is not surprising as there exist natural boron compounds with inherent antibacterial, antiviral and anticancer activity, and boric acid has been used as antiseptic agent in pharmaceutical formulations over a hundred years [10,11]. Boromycin is a macrolide antibiotic from Streptomyces antibioticus, which damages the bacterial cell membrane and acts bactericidal. Boromycin also arrests the cell cycle of tumor cells and increases their chemosensitivity to antineoplastic agents [11]. Boron-containing antibiotic tartrolons (boromycin and aplasmomycin) from the myxobacterium Sorangium cellulosum [12] have antiviral and anticancer efficacies [11]. Borophycin, a polyketide molecule from Nostoc species exerted antitumor efficacy on several cancer cell lines [11]. Calcium fructoborate is an edible natural product from plants, which also exerts antioxidant and anticancer activities [11]. Boron also seems to accelarate wound healing and extracellular matrix turnover; indeed, treatment of deep wounds with a 3% boric acid solution shortened the interval of intensive care-requirement by about 66% [13].
Deep sequencing of biofilm microbiomes on dental composite materials
Published in Journal of Oral Microbiology, 2019
Georg Conrads, Laura Katharina Wendt, Franziska Hetrodt, Zhi-Luo Deng, Dietmar Pieper, Mohamed M. H. Abdelbary, Andree Barg, Irene Wagner-Döbler, Christian Apel
The concept of aesthetic and minimally invasive dentistry has led to the preferred use of direct restorative materials. However, light-curing composite materials possess special characteristics that may reduce their lifespan compared to other filling materials such as amalgam and gold. The clinical success of such composites is hindered by shrinkage, technique sensitivity, and the absence of antibacterial properties. Restoration longevity is closely linked to susceptibility towards bacterial colonization. There is growing evidence that complex bidirectional interactions between the biodegradation of composite resins and bacterial colonization (with acid production and lower pH levels) increases the rate of secondary caries, the most frequent reason for restoration failure [1,2]. Saliva and oral bacteria such as Streptococcus mutans display esterase activity, which accelerate the breakdown of the resin–tooth interface [3,4]. The development of strategies to enhance the stability of composite resins within the oral cavity therefore requires detailed information about bacterial colonisation. Bacteria adhere more strongly to composites than other dental materials [5,6] but the qualitative and quantitative shift in bacterial taxa in vivo has not been investigated in detail. Streptococci play a major role in plaque biofilm formation, with the highly cariogenic species S. mutans involved in the later stages of this process [7,8]. The biostability of dental materials can be increased by inhibiting bacterial adhesion [1]. For example, carolacton is a macrolide keto-carboxylic acid produced by the myxobacterium Sorangium cellulosum and was shown to reduce the viability of S. mutans biofilm cells [9,10]. We have previously incorporated carolacton into a composite resin and demonstrated a significant biofilm-damaging effect in vitro [11]. Here we used Illumina next-generation sequencing to analyse the biofilm microbiome attached to composite materials worn in vivo by human volunteers. We also collected clinically relevant information about the potential antimicrobial effect of carolacton on complex oral communities. Because carolacton is not approved as a drug, we developed a new method for the ex vivo maintenance of biofilms from the saliva of the same volunteers, and tested the influence of carolacton using this model. Our study is the first to identify and compare biofilm microbiomes on composite materials in vivo and in vitro.