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Zhang, Huichun. "Metal oxide-facilitated oxidation of antibacterial agents." Diss., Available online, Georgia Institute of Technology, 2004:, 2004. http://etd.gatech.edu/theses/available/etd-07072004-152317/unrestricted/zhang%5Fhuichun%5F200407%5Fphd.pdf.
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Thesis (Ph. D.)--School of Civil and Environmental Engineering, Georgia Institute of Technology, 2005. Directed by Ching-Hua Huang.<br>Wine, Paul, Committee Member ; Pavlostathis, Spyros, Committee Member ; Mulholland, James, Committee Member ; Yiacoumi, Sotira, Committee Member ; Huang, Ching-Hua, Committee Chair. Includes bibliographical references.
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Tan, Jinlong. "Design and Synthesis of Novel Antibacterial Agents." Thesis, The University of Sydney, 2021. https://hdl.handle.net/2123/25809.
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The latest data on antimicrobial resistance (AMR) related mortality is alarming. A conservative estimate places current global death due to AMR infections at 700,000 annually and projections anticipate that this could rise to 10 million by 2050. Over 50 major initiatives have emerged from the European Union (EU), United Kingdom (UK) and the United States of America (US) since 2007 aimed at improving surveillance, stewardship, and refreshing the drug development pipeline. The identification of priority pathogens, such as the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens has also assisted in directing global attention and efforts towards developing agents against these dangerous microbes. However, despite the FDA approval of 17 new antimicrobial agents since 2013, no novel class of Gram negative active agents has been introduced. Concerning the antibacterials in the drug development pipeline which are currently in phase 3 development or near obtaining approval (fourteen), only one (cefiderocol, a cephalosporin derivative) displays broad activity against priority Gram negative pathogens whilst seven display very specific activity against the same – none of these are new classes.
Fragment-based drug discovery (FBDD) is an efficient strategy to utilise in this research. FBDD involves virtual screening of exceptionally small ligands, termed fragments, against the crystal structure of the target protein. Fragments are known to sample chemical space more efficiently than conventional virtual screening ligand libraries. Fragment hits may have low affinity initially but demonstrate a good amount of free energy of binding per heavy atom, referred to as ligand efficiency. It is then necessary to optimise the best scoring fragments by introducing structural modifications to improve affinity and pharmacokinetic properties towards more drug-like leads.
Chapter 2 of this thesis details the design of novel Extended Spectrum β-lactamase (ESBL) inhibitors through FBDD. This begins with a discussion regarding the benefits and rationale of virtual screening, followed by details of the software and methods used by the candidate to generate drug-like small molecules against protein crystal structures of the target carbapenemase, New Delhi Metallo-β-lactamase 1 (NDM-1). Careful and rational optimisation of high scoring fragments resulted in a structurally diverse set of lead compounds with anticipated ability to restore carbapenem activity in pathogenic bacterial which express NDM-1. Furthermore, we aimed to synthesise a structural extension of lead compounds to provide a prodrug form which we hypothesised could improve effectiveness of the lead compound in Gram negative bacteria. Previously published bacteria detection and identification research by the Groundwater research group targeted an aminopeptidase widely distributed in Gram negative bacteria for differentiating between Gram negative and Gram positive species from clinical isolates. This enzyme, L-alanyl aminopeptidase, cleaved chromogenic compounds containing a terminal L-alanine amino acid residue, which released the chromophore and produced colouration of the colony. Therefore, these ‘L-alanyl precursors’ allowed for distinction between Gram positive and Gram negative bacteria in clinical isolates. We proposed that L-alanyl derivatives of the lead compounds could produce the same effect, effectively targeting the antibacterial agents towards Gram negative species, which are of greater clinical urgency. The compounds which were successfully synthesised were tested by international collaborators and, separately, by the candidate against two clinically important Gram negative pathogens. Inhibition of the target carbapenemase was determined by observed improvement of carbapenem MIC (in this case meropenem) and, therefore, required testing of the synthesised inhibitors in tandem with the carbapenem, by simultaneous broth microdilution. All synthesised compounds displayed the ability to improve meropenem MIC by at least two-fold (that is, the MIC of meropenem halved in the presence of a test inhibitor) and demonstrated no growth inhibition in the absence of meropenem at the concentrations tested. Particularly noteworthy was the performance of L-proline-based compounds, derived from fragment 1, which displayed impressive activity. The thiol-containing L-proline derivative 8 was able to improve the MIC of meropenem by sixteen-fold (i.e. from 64 µg/mL to 4 µg/mL). The L-alanyl prodrug forms of the lead compounds also, generally, demonstrated greater potency than their respective parent lead compounds. In the case of one pair, the prodrug form was seven-times more effective than the corresponding lead compound.
Chapter 3 of this thesis details the use of rational structure modification to generate improved antibacterials based on agents discovered by previous PhD candidates (Dr Liao and Dr Lin) within the research group. The target of this work was Filamenting temperature-sensitive mutant Z (FtsZ), an enzyme ubiquitous in bacteria which is critical for successful cell division and replication. FtsZ inhibitors are a validated antibacterial target, with one such inhibitor, TXA707 and its prodrug TXA709, currently in Phase 1 clinical trials. Research by Dr Liao and Dr Lin identified curcumin-based compounds 88 and 89 respectively which were successful antibacterial agents in Bacillus subtilis, a Gram positive species. The work described in Chapter 3 of this thesis aimed to introduce structural modifications to these compounds to produce less chemically reactive derivatives which retained, or, ideally, improved antibacterial activity. This resulted in the phenolic derivatives which demonstrated comparable activity against B. subtilis. However, these compounds demonstrated no significant activity against a Gram negative species of bacteria, Escherichia coli. Consequently, an L-alanyl prodrug form of the lead phenol 94 was vehemently pursued.
In summary, this thesis details the exploration of a diverse range of synthetic reactions which produced structurally diverse potential antibacterial agents. Many of these compounds exhibited encouraging antimicrobial activity, either by inhibiting a resistance-conferring enzyme (NDM-1) or by inhibiting an enzyme critical for bacterial division (FtsZ).
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Marshall, Neil J. "Antibacterial agents designed to exploit peptide transport systems." Thesis, Bangor University, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.262012.
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Penishkevich, Ya. "Ophthalmic topical antibacterial agents: current and evolving options." Thesis, БДМУ, 2020. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/18146.
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Smith, Nichola Ann. "Photoactivatable Ru(II) polypyridyl complexes as antibacterial agents." Thesis, University of Warwick, 2015. http://wrap.warwick.ac.uk/76173/.
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Novel photoactive ruthenium(II) complexes were designed to incorporate existing anti-tuberculosis drugs, isoniazid and nicotinamide, that could be released from the ruthenium(II) cage by photoactivation with visible light. Two sets of complexes were synthesised based on cis-[Ru(N-N')2(L)2][PF6]2and cis-[Ru(N-N')2(L)X][PF6], where N-N' is 2,2'-bipyridine (bpy) or 1,10-phenanthroline (phen), L is isoniazid (INH) or nicotinamide (NA) and X is either Cl or I. Their dynamic behaviour in solution was explored using NMR to probe the presence of atropisomers. In the case of cis-[Ru(bpy)2(NA)Cl][PF6] (1) and cis-[Ru(bpy)2(NA)I][PF6] (2), the rotation of NA is hindered on the NMR timescale at room temperature, behaviour that was surprisingly not observed for cis-[Ru(bpy)2(NA)2][PF6]2 (5). The hindered rotation was explored by computational methods (DFT) and revealed that hydrogen bonding between the halide and protons of the NA ligand hindered the rotation. The photochemical properties of the Ru(II) complexes were explored by UV-visible spectroscopy and liquid chromatography. All cis-[Ru(N-N')2(L)2][PF6]2complexes in aqueous solution release one ligand, L, in under 1 min using a blue LED (λirr = 463 nm, 50 mW cm- 2 ) to form the photoproduct cis-[Ru(N-N')2(L)(H2O)] 2+ . Continued photoirradiation releases a second ligand, L, with the production of various Ru(II) and Ru(III) aqua photoproducts (with both cis and trans geometry). Interestingly their production was dependent on the power of the light source. Complementary computational studies (DFT/TD-DFT) were utilised to understand structure-activity relationships with respect to photoactivity. The results from the calculations suggest that the number of key electronic transitions (notably1 MLCT) and the favourable leaving properties of the ligand, L, influence the rate of photorelease. In the latter case, a stronger p-accepting leaving ligand shifts the dissociative 3 MC state to lower energy, thus promoting more efficient ligand release. The photobiological properties of the Ru(II) complexes were explored by investigating binding to biomolecules and screening their antibacterial activity in vitro. The complex cis-[Ru(bpy)2(INH)2][PF6]2 (4) binds to the nucleobase 9-ethylguanine (9-EtG) after photoirradiation with a blue LED to produce cis-[Ru(bpy)2(INH)(9-EtG)] 2+ , however reaction with the amino acid L-cysteine was not observed. A 96-array blue LED (λirr = 465 nm, 20 mW cm-2 ) and 32-array multi-coloured LED (λirr = 465 nm, 520 nm, 589 nm and 625 nm, 5 mW cm-2 ) were designed in-house to screen the activity of the complexes in vitro. Their design and construction is described in detail. When tested against Mycobacterium smegmatis (a model for Mycobacterium tuberculosis), complexes cis-[Ru(bpy)2(INH)2][PF6]2 (4) and cis-[Ru(phen)2(INH)2][PF6]2 (6) showed the greatest activity upon photoirradiation for 1 min with a blue LED, with at least a 3x increase in potency when compared to the ligand alone, INH. Most importantly the complexes are inactive in the dark, showing that the antibacterial ligand is selectively released in vitro after photoirradiation. The complex cis-[Ru(bpy)2(MOPEP)2][PF6]2 (9), where MOPEP is 4-[2-(4-methoxyphenyl)ethynyl]pyridine, was initially designed to study two-photon activation via a femtosecond-pulsed laser. Surprisingly the complex was one-photon active with 600 nm and 800 nm light, due to the MOPEP ligand extending and increasing the intensity of the one-photon absorption band shoulder in the 600-800 nm region.
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Nielsen, Elisabet I. "Pharmacometric Models for Antibacterial Agents to Improve Dosing Strategies." Doctoral thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-144909.
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Antibiotics are among the most commonly prescribed drugs. Although the majority of these drugs were developed several decades ago, optimal dosage (dose, dosing interval and treatment duration) have still not been well defined. This thesis focuses on the development and evaluation of pharmacometric models that can be used as tools in the establishment of improved dosing strategies for novel and already clinically available antibacterial drugs. Infectious diseases are common causes of death in preterm and term newborn infants. A population pharmacokinetic (PK) model for gentamicin was developed based on data from a prospective study. Body-weight and age (gestational and post-natal age) were found to be major factors contributing to variability in gentamicin clearance and therefore important patient characteristics to consider for improved dosing regimens. A semi-mechanistic pharmacokinetic-pharmacodynamic (PKPD) model was also developed, to characterize in vitro bacterial growth and killing kinetics following exposure to six antibacterial drugs, representing a broad selection of mechanisms of action and PK as well as PD characteristics. The model performed well in describing a wide range of static and dynamic drug exposures and was easily applied to other bacterial strains and antibiotics. It is, therefore, likely to find application in early drug development programs. Dosing of antibiotics is usually based on summary endpoints such as the PK/PD indices. Predictions based on the PKPD model showed that the commonly used PK/PD indices were well identified for all investigated drugs, supporting that models based on in vitro data can be predictive of antibacterial effects observed in vivo. However, the PK/PD indices were sensitive to the study conditions and were not always consistent between patient populations. The PK/PD indices may therefore extrapolate poorly across sub-populations. A semi-mechanistic modeling approach, utilizing the type of models described here, may thus have higher predictive value in a dose optimization tailored to specific patient populations.
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Das, Sanjan Kumar. "Application of Structural Genomics for Developing Novel Antibacterial Agents." Thesis, University of Sheffield, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.486462.
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The structure-based design of novel antibiotics has great potentiaL To achieve this goal the first step is to gather structural information on relevant proteins and utilise this to find inhibitors through a process of screening and subsequent optimising using structural data. In this· pilot study a number of essential gene products from Bacillus subtilis were targeted for structural studies where homologues were present in pathogenic microorganisms. In the initial analysis 41 essential genes of unknown structure or function were selected for structure determination. From this list 9 genes were rejected as their protein products were assigned as possible membrane proteins by hydropathy analysis. From the remaining 32 genes on the list 12 (ysxC, thiD, ywaF, ydiC, ydiE, yrrA, yabH, ylxR, yqiB, yacN, ymjL and luxS) were selected for study as part of this thesis. Recombinant DNA technology was used to produce pure protein for crystallisation trials and subsequent structure determination by X-ray crystallography. Successful overexpression was achieved for 8 of the protein targets ofwhich 7 were found to be soluble. 6 ofthese were taken forward for crystallisation as part of this work with the 7th being·pursued by another member of the laboratory due to project overlap. Of these 6 proteins 5 were successfully purified and crystallised (LuxS, YsxC, YacN, YabH, and ThiD) and structures were determined for all but ThiD. The successful crystallisation of all of the 5 soluble proteins was unexpected and maybe related to the characteristics of the structure determination pipeline which requires the expression of the protein product in a soluble form and at high leveL This may result in the selection of proteins with a higher tendency to crystallise. The gene to structure conversion rate'obtained here (33%) is equivalent to that obtained for the overall programme on all 32 genes (34%) suggesting that 4 bacterial proteins 1/3rd of the proteome can be analysed as part of a structural genomics programme.
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Griffiths, Jennifer Mary. "Model systems to investigate bacterial persistence to antibacterial agents." Thesis, University of Leeds, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.590484.
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Bacterial persistence describes the phenotypic variation displayed by clonal bacterial populations which permits a small fraction of cells to survive exposure to antimicrobials. The phenomenon was first described in the 19405 by Joseph Bigger who observed that penicillin could not sterilize a culture of Staphylococcus aureus. The surviving cells were not resistant mutants as they displayed equal susceptibility to penicillin as the parent population upon subculture. Among the various hypotheses which have been proposed to explain this phenomenon, the majority consider persisters to be dormant The prevailing model in Escherichia coli is that this behaviour results from stochastic expression of the toxic portion of chromosomal toxin-antitoxin modules. However, the exact mechanisms underlying this behaviour remain elusive, partly owing to the apparent redundancy of this phenotype. Persistence has been observed in all bacterial species tested to date however, most studies have focused on E. coli. This study aimed to explore the mechanisms of persistence in S. aureus by characterising two transposon insertion mutants identified as being defective in persistence to antimicrobials. The mutants were affected in different ABC transporter-like proteins, AbcA and PapA. The role of ABC transporters in persistence was further evaluated by independently inactivating abcA and papA. The resulting strains exhibited a reduced-persister phenotype to antimicrobials from different classes supporting a role for AbcA and PapA in S. aureus perSistence. The second part of this study sought to investigate the use of mycoplasmae as model systems for investigating persistence. Time-kill studies established that Mycoplasma hominis and Mycoplasma galliseptcium do generate persister cells. As neither organism has toxin-antitoxin modules in their genomes, the results imply that other mechanisms for persistence must exist. These mechanisms were investigated by generating and screening a M, gallisepticum transposon insertion library for genes involved in persistence. Four mutants with reduced persistence, disrupted in spoT, vlhA 1.04, asnA and MGA_0126, were identified.
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Carraco, Moreira Joao Bruno. "Characterisation of symmetric bis-benzimidazoles as antibacterial chemotherapeutic agents." Thesis, University of London, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.579712.
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Nosocomial and community-acquired infections due to methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria are associated with high levels of mortality, morbidity and significant social and economic costs in the U.K. and elsewhere. As the evolution of multi-drug resistance relentlessly erodes the utility of currently available antibacterial drugs, it is essential to maintain efforts to search for new classes of antibacterial agents. Benzimidazoles are potent antihelmintic agents discovered in 1961. Chemical modifications led to the synthesis of the head-to-tail fluorochrome Hoechst 33258 and, more recently, to symmetric head-to-head bis-benzimidazoles (sBBZ). The antibacterial potential of these compounds was examined. Antibacterial activity was evaluated by minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assays using a total of 143 Gram-positive isolates, including 61 MRSA, 12 vancomycin resistant enterococci (VRE), 12 Streptococcus pneumoniae, 11 Listeria monocytogenes, 7 Mycobacterium spp. (including Mycobacterium tuberculosis) and 14 Gram-negative isolates. Structure-activity relationships were determined and key requirements for activity were identified. Acute toxicity of sBBZs was assessed using the sulforhodamine B staining method and a zebrafish embryo model. To clarify mode of action, time kill studies, flow cytometry, DNA microarrays and radioisotope incorporation assays were employed. sBBZs displayed activity against Gram-positive but not Gram-negative pathogens; the most potent compound possessed MIC90 values of 0.06, 0.125 and 1 mg/L against, respectively, MRSA, VRE and M tuberculosis isolates. Data suggests that sBBZs are bacteriostatic agents that interfere primarily with the DNA machinery and do not select for drug resistant variants over a 31-day period of drug exposure. Subtle structural modifications have an incisive effect on in vitro potency of sBBZs. Toxicity was determined as minimal for WI-38 cell line and the zebrafish embryo model of infection. Sub-inhibitory concentrations of sBBZs inhibited MRSA transcription of pathogenicity-associated genes. Symmetric bis-benzimidazoles are new DNA-interfering bacteriostatic agents with potent antibacterial activity and significant therapeutic potential against Gram-positive bacteria, including MRSA and M tuberculosis.
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Lam, Chi-wah. "Antibacterial effects of nanoparticles on cariogenic organisms /." View the Table of Contents & Abstract, 2005. http://sunzi.lib.hku.hk/hkuto/record/B31490414.
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Ismaeel, N. A.-A. "Resistance of Providencia stuartii to chlorhexidine and other antibacterial agents." Thesis, Cardiff University, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376556.
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Baguley, Christina Birgit. "The structure and activity of #beta#-lactamase I from Bacillus cereus." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.279880.
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O'Leary, Ruth. "Investigation into the modification of the A-ring of analogues of 4-quinolones." Thesis, University of Strathclyde, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.303283.
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Shojaee, Aliabadi Fariborz. "Danofloxacin pharmacodynamic and pharmacokinetic interrelationships in ruminant species." Thesis, Royal Veterinary College (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266348.
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Miller, Chandra Tier. "The design, synthesis and screening of naphthalene diimides with antibacterial activity /." Digital version accessible at:, 1999. http://wwwlib.umi.com/cr/utexas/main.
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Hendry, Maureen M. "The efficacy of topical honey to heal wounds and burns : systematic review and meta-analysis /." [St. Lucia, Qld.], 2001. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16941.pdf.
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林志華 and Chi-wah Lam. "Antibacterial effects of nanoparticles on cariogenic organisms." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B45007743.
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Acquaah-Harrison, George. "Antibacterial Agents: 1,4-Disubstituted 1,2,3-Triazole Analogs of the Oxazolidinone." Ohio : Ohio University, 2010. http://www.ohiolink.edu/etd/view.cgi?ohiou1273250347.
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Jackson, Andrew Edward. "A novel approach to #beta#-lactam and quinolone antibacterial agents." Thesis, University of Sunderland, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242127.
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The f)-lactam or azetidinone 4-membered heterocyclic nng system has been synthesised by many different synthetic strategies and these are well documented in the literature. Many of these strategies give substituted azetidinone rings displaying defined stereochemistry which are used as the building block for many modern day antibiotics. It was therefore intended to pursue a method of azetidinone ring formation using cheap and readily available starting materials employing a [2+2] cycloaddition reaction which, according to the literature, had only a few examples and was seen to be an area ripe for research. Taking urethane in anhydrous THF and metalating with n-butyl lithium, followed by the subsequent addition of phenyl vinyl sulfone, it was envisaged that the two would react in such a way to give the -l-membered azetidinone ring. It was found however that the carbon-nitrogen bond was formed but subsequent cyclisation did not follow and therefore no azetidinone was formed. Although azetidinone ring was not detected the novel compound N,N-bis-(phenylsulfonylethyl) urethane was isolated. This compound was of interest since it was hoped that it could provide a new route to substituted pyridines. Various methods were undertaken in an attempt to cyclise this molecule via the generation of a-sulfonyl carbanions and reactions with a variety of electrophiles. During our experiments no cyclised products were detected. TIle replacement of phenyl sulfonyl group with triphenylphosphonium bromide provided a new hope for azetidinone synthesis since its ability to stabilise a-sulfonyl carbanions and promote reaction with electrophiles was well established. Experiments of this nature failed to produce an azetidinone. TIle next stage of research was to investigate a new route to the production of quinolone antibiotics. Quinolones, particularly those which are furnished with a fluorine at C-6 position, are the new generation of antibiotics which exhibit a high activity and selectivity towards pathogens which have become resistant to older antibiotics such as penicillin. Needless to say their importance in the pharmaceutical industry has increased dramatically over recent years and research into the improvement of synthetic strategies towards the total synthesis of these molecules has attracted much commercial interest. Meth-Cohn showed that quinolones can be formed in excellent yield by the reaction of N-alkylformanilides in phosphorus oxychloride and activated acid chlorides e.g. methyl malonyl chloride. This approach is examined regarding the synthesis of both novel and known quinolone antibiotics (norfloxacin and ciprofloxacin). Work on this topic has produced encouraging results with the synthesis of important antibacterial intermediates.
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Salama, Fatma Ibrahim Khalifa. "Exploring the potential of Affimer artificial antibodies as antibacterial agents." Thesis, University of Leeds, 2017. http://etheses.whiterose.ac.uk/19935/.
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Glansdorp, Freija Gwendolyn. "Chemical studies into novel modes of action of antibacterial agents." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611932.
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Kasturiarachchi, Jagath Chandana. "Bio-oligomers as antibacterial agents and strategies for bacterial detection." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/10030.
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In this thesis I examined the potential of Bio-Oligomers such as peptoids, peptides and aptamers, as therapeutic and diagnostic entities. Therapeutic Bio-Oligomers; A series of peptoid analogs have been designed and synthesised using solid phase synthesis. These peptoids have been subjected to biological evaluation to determine structure-activity relationships that define their antimicrobial activity. In total 13 peptoids were synthesised. Out of 13 different peptoids, only one peptoid called Tosyl-Octyl-Peptoid (TOP) demonstrated significant broad-spectrum bactericidal activity. TOP kills bacteria under non-dividing and dividing conditions. The Minimum Inhibitory Concentrations (MIC) values of TOP for S. epidermidis, E. coli and Klebsiella were 20 μM, whereas Methicillin-resistant Staphylococcus aureus (MRSA) and Methicillin-sensitive Staphylococcus aureus (MSSA) were 40 μM. The highest MIC values were observed for Pseudomonas aeruginosa (PAO1) at 80 μM. The selectivity ratio (SR) or Therapeutic index (TI) was calculated, by dividing the 10% haemolysis activity (5 mM) by the median of the MIC (50 μM) yielding a TI for TOP as 100. This TI is well above previously reported peptidomimetics TI of around 20. TOP demonstrates selective bacterial killing in co-culture systems and intracellular bacterial killing activity. Diagnostic Bio-Oligomers; In the second part of my thesis, I investigated aptamer and peptide-based molecular probes to detect MRSA. As well as screening aptamers and peptide probes against whole MRSA, I over-expressed and purified PBP2A protein. This purified protein was used as a target for aptamer and peptide probes to detect MRSA. Two different aptamer libraries were initially screened for utility. In-vitro conditions for SELEX were optimised. Biopanning with a phage derived peptides was also performed. Target sequences for both methods were identified and chemically synthesised. Evaluation of fluorescently labelled sequences with flow cytometry and confocal imaging showed no specificity for MRSA detection with either method. The Bio-Oligomers and the in-vitro selection methodology require further refinement to improve diagnostic utility.
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Carrick, Christopher. "Exploiting bacterial transporters for the design of novel antibacterial agents." Thesis, University of York, 2014. http://etheses.whiterose.ac.uk/6533/.
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The alarming increase in the occurrence of antimicrobial resistance has led to a situation whereby some strains are untreatable by known antimicrobials. The Trojan horse strategy is one methodology with the potential to overcome the rising tide of resistance. Work was undertaken to synthesise two different Trojan horses. One based on an analogue of the Bacillus siderophore petrobactin, the other a novel compound prepared using the Ugi four component condensation. Both contained a fluoroquinolone antimicrobial; ciprofloxacin. Additionally a series of bis-catecholate ligands were prepared for use as iron chelating antimicrobial agents. The Trojan horse based on the Ugi four component condensation was screened against wild type E. coli and was found to have antibacterial activity, but at a lower level than the parent drug ciprofloxacin. The mechanism of action was determined by performing a DNA gyrase assay, which confirmed the conjugate was inhibiting E. coli DNA gyrase activity. A set of three glycosylated fluoroquinolones was screened, to assess the extent to which they were actively transported. Experiments were performed using glucose and galactose as carbon sources, with E. coli strains deficient in galactose transport. Further experiments with outer membrane porins (OMPs) mutants were also performed. The results suggested that the conjugates were not actively transported, but were gaining access to the cells via the OMPs. Studies were undertaken on the bis-catecholate ligands to assess their suitability as potential antimicrobial agents. However, stability studies showed that one set of ligands was highly unstable due to hydrolysis and oxidation, and therefore not viable for use. The asymmetric ligand showed promising activity in vitro however electrochemical studies indicated it was susceptible to oxidation. Consequently, the active species could not be reliably determined. Further study is required to establish its identity.
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Zhang, Jianjun. "Library Synthesis of Anticancer and Antibacterial Agents via Azide Chemistry." DigitalCommons@USU, 2010. https://digitalcommons.usu.edu/etd/711.
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Various anticancer and antibacterial agents have been synthesized via azide chemistry by taking advantage of carbohydrate. Starting from the synthesis of 14 glycosyl azides, a library of carbohydrate-oxazolidinone conjugates and a library of carbohydrate-cyclopamine conjugates with biological interests were synthesized based on a highly efficient "click reaction" assisted by sonication. Some of the conjugates have improved solubility and enhanced anticancer activity. A library of neomycin B derivatives with various modifications at the 5" position has been synthesized. Two leads exhibit prominent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Antibacterial activities were measured when combined with other clinically used antibiotics and significant synergistic activities were observed. Three different classes of aryl N-glycosides have been synthesized by employing 1,4-naphthoquinone and glycosyl azides undergoing a [2+3] cycloaddition. Alkyl azides can also undergo the same cycloaddition. After the removal of the protecting group, a library of 9,10-anthraquinone derivatives with potential anticancer activity and a library of 2-aminomethylene-1,3-indanediones with novel antibacterial activity have been developed, respectively. A one-pot three-component [2+3] cycloaddition for the synthesis of 1-alkyl 1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione and 2-alkyl 2H-naphtho[2,3-d][1,2,3] triazole-4,9-dione has been developed. By taking the advantage of their difference in basicity, both products can be obtained in good purity. Using an allylic azide rearrangement, a convenient method has been developed for the synthesis of several 2',3'-dideoxyaminoglycosides. The antibacterial activity of these novel aminoglycosides also confirms the indispensable role of the 2'-NH2 group for both neomycin and kanamycin classes of aminoglycosides. A novel structural motif containing the hexylaminocarbonyl groups at O-5 and/or O-6 of 2',3'-dideoxyneamine could lead to the production of new aminoglycosides against resistant bacteria.
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Chiodini, G. "SYNTHESIS AND DEVELOPMENT OF NEW ANTIBACTERIAL AGENTS INHIBITORS OF FTSZ." Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/232409.
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Elements of the bacterial cytoskeleton represent potential targets for antimicrobial compounds. FtsZ (Filamentous temperature sensitive Z) is a bacterial ancestor of eukaryotic tubulin. It possess markedly different structures than its eukaryotic analogue, making possible to develop specific inhibitors for the bacterial protein. The 3-methoxybenzamide (3-MBA) has a weak antibacterial activity against B. subtilis, it can easily penetrate bacterial cell and bind FtsZ at high ligand efficiency. The fluorinated 3-MBA analogue 2,6-difluoro-3-nonyloxybenzamide (compound 1) showed a significant activity against B. subtilis and S. aureus. Starting from the compound 1 we designed and synthesized a new series of derivatives that replaced the amide function with bioisosteric groups and new compounds differently substituted at the 3 position of the 2,6-difluoro-3-hydroxybenzamide.
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Tshanga, Siphokazi Sisanda. "Antibacterial activity of liposome encapsulated cyclo(TYR-PRO)." Thesis, Nelson Mandela Metropolitan University, 2011. http://hdl.handle.net/10948/1450.
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Cyclic dipeptides (CDPs) are amino acid-based compounds, some of which possess antibacterial activity. The encapsulation of certain drugs into liposomes has been found to improve their activity in terms of bioavailability and duration of action. Liposomes are small vesicles that are under investigation as drug carriers for the delivery of therapeutic agents. A number of liposome formulations are currently under clinical trial review, whilst some have already been approved for clinical use. The aim of this study was to optimize a liposomal cyclo(Tyr-Pro) formulation and to assess its antibacterial activity against various Gram-positive and Gram-negative bacteria. Response surface methodology (RSM) using the central composite design (CCD) model was used to optimize liposomal formulations of cyclo(Tyr-Pro) for each of the four bacteria, namely Bacillus cereus, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Percent drug encapsulated and bacterial inhibition were investigated with respect to two independent variables, i.e. lipid composition and cholesterol content. Design Expert 8 was used for the purpose of finding the combination of independent variables that would yield an optimal formulation for each bacterium. The model selected by the software failed to adequately correlate the predicted models to the experimental data. The in vitro experiments showed that the antibacterial activity of liposome-encapsulated cyclo(Tyr-Pro) was superior to that of its free counterpart. Binding maximum or Bmax for the encapsulated compound at concentrations as low as 0.412 mg/ml, was significantly higher than that obtained for free cyclo(Tyr-Pro) which was tested at a concentration of 20 mg/ml. Furthermore, encapsulation of cyclo(Tyr-Pro) into a liposome formulation enhanced its potency. This was evident in the lower IC50 values for the liposomal compound when compared to free cyclo(Tyr-Pro).
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Shapiro, Elyse M. "Optimizing Escherichia coli for the detection of antimicrobial compounds /." Thesis, Connect to this title online; UW restricted, 2005. http://hdl.handle.net/1773/9916.
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Spencer, William T. "Part I, studies toward the total synthesis of Trocheliophorolide A. ; part II, studies on the development of a palladium-catalyzed carbonylative cross-coupling towards the synthesis of alkenyl alkynyl ketones /." Online version of thesis, 2008. http://hdl.handle.net/1850/7729.
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Rigoreau, Laurent Jean Martin. "The synthesis of β-Sultams." Thesis, University of Huddersfield, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323939.
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El-Falaha, B. M. A. "Resistance to antibacterial agents : studies with Escherichia coli and Pseudomonas aeruginosa." Thesis, Cardiff University, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304154.
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Ella-Menye, Jean-Rene. "Synthesis of Novel Chiral Heterocyclic Compounds for Antibacterial Agents and Peptidomimetics." ScholarWorks@UNO, 2007. http://scholarworks.uno.edu/td/611.
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Small chiral molecules are very important building blocks in the synthesis of biologically active compounds. These building blocks include nitrogen and oxygen-containing heterocycles such as 2-oxazolidinones, 1,3-oxazinan-2-ones, 2-oxazolines, oxazines, morpholine and morpholinones. Because of their interesting properties, chiral heterocycles have stirred great interest in the synthetic chemist community to develop useful and efficient strategies to these molecules. In this dissertation, the design and syntheses of various heterocyclic building blocks are presented, as well as the testing of their biological activities as antibacterial. Another very interesting family of heterocycle-containing molecules are the Aeruginosins. They are a family of marine natural products isolated from a blue-green algae, which display inhibitory activity against serine proteases such as thrombin, trypsin, and factor VIIa. Most aeruginosins contain an heterocyclic moiety called the 2-carboxy-6-hydroxyoctahydroindole (Choi) ring; this Choi moiety is a rigid bicyclic unnatural amino acid and is the core structure in the aeruginosins, indispensable to their biological activity. A synthesis of a ring-oxygenated variant of the Choi from D-mannose is reported in this dissertation. The ring-oxygenated variant of 2-carboxy-6-hydroxyoctahydroindole can potentially be used as a surrogate of Choi in the design and synthesis of aeruginosin-based thrombin inhibitors.
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Doss, Sally. "The role of antibacterial agents on the pathogenicity of Staphylococcus aureus." Thesis, University of Edinburgh, 1992. http://hdl.handle.net/1842/19698.
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<i>Staphylococcus aureus</i> is a pathogenic bacterium which has an impressive armoury of extracellular toxic factors. In recent years, <i>S. aureus</i> has developed resistance to the new 4-quinolone antibacterials. Since this resistance is a result of a chromosomal mutation, it was proposed that the resistant bacteria might be less pathogenic. This thesis has studied this postulate. Ciprofloxacin sensitive and resistant strains of <i>S.aureus</i> were compared to establish any differences in their respective production of virulence factors both <i>in vitro</i> and <i>in vivo</i>. Since <i>S.aureus</i> produces a large number of virulence factors, four were studied in detail; coagulase, Protein A, alpha and delta toxin. The <i>in vitro</i> production of the four factors by ciprofloxacin sensitive and resistant strains was investigated in the presence and absence of 1/4 and 1/2 Minimum Inhibitory Concentrations (MIC) levels of six antibiotics: ciprofloxacin, enoxacin, methicillin, gentamicin, chloramphenicol and tetracycline. The production of soluble and bound coagulase was measured by a chromogenic substrate assay. The production of bound and soluble Protein A, alpha toxin and delta toxin were measured by ELISAs. In the absence of the antibiotics, the production of the four virulence factors was similar in the sensitive and resistant strains. The acquisition of ciprofloxacin resistance did not affect the production of these factors. Conversely, the presence of 1/4 and 1/2 MIC levels of gentamicin, chloramphenicol and tetracycline reduced the production of both bound and soluble coagulase, and bound and soluble Protein A, in both sensitive and resistant strains. In the presence of 1/2 MIC levels of ciprofloxacin, enoxacin, gentamicin, chloramphenicol and tetracylcine, the production of alpha and delta toxins was reduced and in some cases completely inhibited. The presence of 1/4 MIC levels of the antibiotics had a reduced effect on the inhibition of the toxins. The presence of 1/4 and 1/2 MIC levels of methicillin both increased the production of the toxins, though the increase was less significant in the presence of 1/4 MIC levels.
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Bandara, Bandarage Mahesh Kithsiri Optometry & Vision Science Faculty of Science UNSW. "Investigation and characterisation of antibacterial properties of non-steroidal anti-inflammatory drugs." Awarded by:University of New South Wales. School of Optometry and Vision Science, 2005. http://handle.unsw.edu.au/1959.4/22284.
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Microbial contamination of contact lenses is a significant risk factor leading to adverse responses. Adhesion of microorganisms to a contact lens is the first step in a series of events that leads to contact lens-related infections or inflammation. Recently, some of the non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to have the ability to interfere with microbial biofilm formation. In this project, antibacterial properties of commonly used NSAIDs (salicylic acid, sodium diclofenac and ketorolac) were assessed and characterised using biological assays and molecular biological techniques. Salicylic acid, ketorolac and diclofenac reduced adhesion of a range of bacterial species isolated from corneal infection and inflammatory events to contact lenses in a dose-dependent manner. Salicylic acid also decreased the adhesion of Pseudomonas aeruginosa and Staphylococcus epidermidis to human corneal epithelial cells in a dose-dependent manner. Results further demonstrated that NSAIDs had a significant impact on the production of virulence factors such as Type IV pili mediated (twitching) motility, flagella mediated swimming, elastase, protease IV and alkaline protease and affected the production of acylated homoserine lactones of P. aeruginosa. Salicylic acid and ketorolac affect the expression of P. aeruginosa outer membrane proteins. In the presence of the salicylic acid and ketorolac more than 85% of all detectable outer membrane proteins changed and most were down-regulated. Moreover, in the presence of salicylic acid at least five gene products, including Na+ - translocating NADH (Nrq1), choline dehydrogenase (CHDH), a hypothetical protein of unknown function, a gene product with no similarity to any known sequence in the database and a sequence similar to 23S rRNA of P. aeruginosa, were down-regulated. The results of this study clearly demonstrated that NSAIDs have a significant impact on virulence factors and the expression of acylated homoserine lactones by P. aeruginosa. This thesis has illustrated the potential of NSAIDs for preventing bacterial contamination of contact lenses by ocular pathogens and highlights the potential for NSAIDs as antibacterial agents. Therefore, this class of compound should be investigated further for their therapeutic efficacy in vivo.
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Carlsson, Stefan. "Antibacterial effects of nitrite in urine /." Stockholm : Karolinska institutet, 2005. http://diss.kib.ki.se/2005/91-7140-237-3.
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Singh, G. "Antibacterial activity testing of cotton medical textiles sonochemically impregnated with metal oxide nanoparticles." Thesis, Coventry University, 2014. http://curve.coventry.ac.uk/open/items/edeb833b-a792-49eb-bc22-bafbd374bb22/1.
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The Sonochemistry Centre at Coventry University is one of a group of organisations working on a project to develop a new technology for producing antimicrobial textiles. This technology involves the use of an ultrasonic process (sonochemical) to generate and impregnate fabrics with antibacterial metal oxide nanoparticles. The expectation is that these textiles can be produced at an affordable price for routine use in hospitals as uniforms, curtains, hospital bed sheets and linen. The aim of this PhD project was to assess the antibacterial activity of fabrics impregnated with ZnO and CuO NPs against a variety of Gram positive and Gram negative bacteria. The testing was principally carried out according to the absorption method from ISO 20743:2007. Research was also extended to compare different methods of assessing antibacterial activity of textile fabrics. These included disc diffusion tests and shake flask tests in saline or nutrient broth. Overall the results from absorption tests demonstrated that both the ZnO and CuO impregnated fabrics showed very good levels of antibacterial activity (A>2) against the test bacteria (Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa). During the optimisation of lab scale process to the pilot scale, two different types of CuO fabrics were produced to test and compare the antibacterial activity. One type of fabrics were impregnated with pre-made CuO nanoparticles by a ‘throwing the stones’ technology termed TTS and the other with sonochemically formed nanoparticles (in-situ), same as the lab process. The results indicated that the fabrics impregnated with sonochemically formed NPs displayed better antibacterial activity than the pre-made NPs. Leaching of the antibacterial agents in to saline was investigated using a shake flask method. CuO and ZnO coated fabrics prepared at laboratory scale were tested against Staphylococcus aureus, Acinetobacter baumannii and Escherichia coli. It was found that leachates prepared by shaking the fabrics in saline for 3 hours showed no antibacterial activity for CuO fabrics. However, leachates from ZnO fabrics showed an excellent activity after 24 ± 3 hours against all three bacterial species. Flow cytometry (FC) was investigated as an alternative to standard agar plate count (PC) methods for the determination of viable cell numbers. There was a general agreement between the results from agar plate counts and flow cytometry except that post incubation counts were greater with FC. The higher numbers of viable cells detected with FC may have been due to the presence of viable but not culturable cells (VBNC). Viable cells were observed by fluorescence microscopy in post incubation samples in which no viable cells were detected on nutrient agar plates. Cytotoxicity studies were conducted on ZnO and CuO fabrics from the pilot scale (both in-situ and TTS) against human dermal fibroblast cells (HDF) and human hepatocellular carcinoma cells (HepG2) using a MTT assay to determine cell viability. The results showed that ZnO and CuO are not toxic to HDF cells. However, cytotoxicity was seen in HepG2 cells with cell viability decreasing by > 14% for all the fabrics after 24 hours.
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Mbere, Johana M. "Development of new benzo[b]thiophene amide-based antimicrobial agents." Department of Chemistry - Faculty of Science, 2005. http://ro.uow.edu.au/theses/396.
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The overall aim of this project was to investigate the synthesis and activity of a range of compounds based on the benzo[b]thiophene-2-carboxamide structural motif as potential new antimalarial agents, and to a lesser extent as antibacterial agents.In order to subsequently explore any structure-biological activity relationships, the first part of the project involved the systematic synthesis of some 39 non-fused substituted benzo[b]thiophene amide derivatives including tetrahydroisoquinolines, tetrahydro-β-carbolines, dihydropyrroles, piperazines, piperidines and other bridged ring systems as part of the amide-nitrogen component. Methods for the synthesis of the new amide derivatives were developed based on benzo[b]thiophene acid chloride and amine reactions, or on dicyclohexylcarbodiimide-mediated carboxylic acid amine coupling reactions.Further substitution reactions were also undertaken on tetrahydro-β-carboline amides (55, 56, and 57) with the introduction of an N-benzyl group and an N-onitrobenzyl group in the case of 55. The N-boc protected piperazine amide 63 also served as a precursor for other N-substituted piperazine amide derivatives. A single crystal X-ray structure on amides 63 and 73 confirmed the amide rotamer geometry in the solid state with these compounds.The second part of the project incorporated the synthesis of fused analogues which were more conformationally restricted while still retaining the benzo[b]thiophene amide structural motif. A new free radical cyclisation approach to the benzo[b]thieno[2,3-c]pyridin-1-one system in compound 92 was developed, together with the corresponding model isoquinolinone analogue 95. The reaction was based on the use of tributyltin hydride and AIBN to produce the required free radical intermediate from an arylbromide precursor.The free radical cyclisation reaction was extended to synthesise N-benzyl and substituted N-benzyl analogues of 92. The dihydroxylation of the N-allyl substituent in 92 was achieved using potassium osmate and N-methylmorpholine-N-oxide (NMO). A further free radical cyclisation route to the N-benzo[b]thien-2-oyl derivatives 112 was also achieved.The synthesis of the novel 9-membered ring containing fused derivatives 120 and 121 was also achieved. This synthesis involved ring closing metathesis methodology using the bis-allyl amides 118 and 119 and Grubbs’ I ruthenium catalyst. The polymer supported version of this catalyst gave better yields of the cyclisation products. A single crystal X-ray structure of 120 confirmed the cis geometry of the double bond in the 9-membered ring. In the course of preparing the required precursor 119 for the 9-membered ring synthesis, a new imine allylation reagent combination was discovered involving zinc, allyltributyltin and boron trifluoride etherate. This reaction is worthy of further investigation to determine its wider synthetic utility.Ring closing metathesis reactions also afforded the dihydropyrrole amides 113 and 114 in good yields.A palladium-mediated cyclisation approach to the new benzo[b]thieno[2,3- c]pyrrolo[2,3-a]indol-11-one system in 126 was also accomplished based on the Nacylindoles 124 and 125.A number of the compounds were tested for their possible in vitro antimalarial activity against two strains of Plasmodium falciparum (K1 CB1 and TM4/ 8.2) and two active leads, the benzo[b]thienoquinolinone derivatives 95 and 102, were discovered. Some potential structure-activity trends for the tested benzo[b]thiophene derivatives were observed (Chapter 4).Antibacterial testing of a few benzo[b]thiophene compounds against Staphylococcus aureus and vancomycin-resistant Enterococcus faecium strains was also done, and the benzo[b]thienoquinolinone derivative 92 exhibited promising activity against Staphylococcus aureus.
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Clarke, Annette June Morgan. "The physical characterization and antibacterial activity of herring protamines." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0029/MQ47419.pdf.
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Fleeman, Renee. "Discovering Antibacterial and Anti-Resistance Agents Targeting Multi-Drug Resistant ESKAPE Pathogens." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6839.
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Antibiotic resistance has been a developing problem for mankind in recent decades and multi-drug resistant bacteria are now encountered that are resistant to all treatment options available. In 2014, the World Health Organization announced that this problem is driving us towards a “post-antibiotic era” that will change the face of modern medicine as we know it. If lack of novel antibiotic development and FDA approval continues, by the year 2050, 10 million people will die each year to an antimicrobial resistant bacterial infection. With lack of pharmaceutical industry involvement in developing novel antibiotics, the responsibility now lies within the academic institutions to identify potential novel therapeutics to fuel the antibiotic drug discovery pipeline. Combinatorial chemistry is one technique used to expedite the discovery process by assessing a large chemical space in a relatively short time when compared to traditional screening approaches. Combinatorial libraries can be screened using multiple approaches and has shown successful application towards many disease states. We initially discovered broad spectrum antibacterial bis-cyclic guanidines using combinatorial libraries and expanded on the knowledge of the physiochemical attributes necessary to inhibit Gram negative bacterial pathogens. Following this success, we continued to assess the combinatorial libraries for adjunctive therapeutics that potentiate the activity of obsolete clinical antibiotics. The polyamine efflux pump inhibitors discovered in this subsequent study prove the benefits of using the large chemical space provided in the combinatorial libraries to identify a variety of therapeutics. Our studies always begin with identifying an active compound and active compounds undergo hit-to-lead optimization. This optimization studies are of utmost importance in developing a novel antibacterial agent for therapeutic applications. Our medicinal chemistry work described here is proof of the success of careful structure activity analyses to optimize a hit scaffold to create a more effective antibacterial agent. Overall, our work described here reveals the potential role of academic institutions in fending off the impending “post-antibiotic era”.
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Provost, Paul Graham. "The persistence and effects of antibacterial agents in marine fish farm sediments." Thesis, Edinburgh Napier University, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.369173.
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Pan, Po-Shen. "Synthesis of macrocycles and their biological evaluation as antitumor and antibacterial agents." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2008. http://wwwlib.umi.com/cr/ucsd/fullcit?p3320912.
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Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 2008.<br>Title from first page of PDF file (viewed October 3, 2008). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.
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Meng, Fan Cheng. "Chemical constituents from the rhizome of coptis chinensis and their antibacterial activities." Thesis, University of Macau, 2018. http://umaclib3.umac.mo/record=b3953272.
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Mariner, Katherine Ruth. "The activity, mode of action and generation of resistance to novel antibacterial agents." Thesis, University of Leeds, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.659123.
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The failure of antibiotics to treat infections caused by multi-drug resistant bacteria is a significant problem in the field of antimicrobial chemotherapy. The characterisation and development of antibacterial agents displaying novel modes of action (MOAs) or the modification of existing antibiotic scaffolds may address this problem. This study therefore sought to identify antibiotic candidates, establishing their antibacterial activity, bacterial specificity, MOA and propensity for resistance development. From nearly half a million compounds which were screened in silica against RNA polymerase (RNAP), D-alanine: D-alanine ligase and peptidoglycan transglycosylases, no inhibitors with specific activity against their target were identified, which highlights the difficulties of developing novel antibacterial agents. However, targeted inhibition of the cell envelope and RNAP were observed for the type B lantibiotic derivative NVB353 and corallopyronin A, respectively. The former may show greater promise as a chemotherapeutic candidate, due to lower propensity for resistance development. In addition, a number of compounds which appear to damage the bacterial cell membrane specifically were identified, and which may be suitable for treatment of persistent bacterial infections. Transcriptional profiling of Staphylococcus aureus treated with a panel of known membrane damagers was also used to identify upregulafed genes which might be potential candidates for future development of biosensors solely responsive to membrane damage. These biosensors could be used to eliminate compounds which are likely to cause non-specific toxic side effects if administered to humans, but may also identify membrane damaging agents that could be developed for clinical use should they show bacterial specificity.
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Gonciarz, Ryan Lennox. "Broadening the spectrum of antibacterial agents to tackle multidrug-resistant Gram-negative pathogens." Thesis, University of Leeds, 2018. http://etheses.whiterose.ac.uk/22308/.
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Antimicrobial resistance is one of the greatest threats to human health in the 21st century: particularly resistance amongst Gram-negative bacteria. The work presented herein aims to identify new agents that target drug-resistant Gram-negative pathogens such as E. coli, through the rational modification of the oxazolidinone class of antibiotics. This class, exemplified by linezolid, is well validated for treating Gram-positive derived infections, but lacks clinically-useful activity against Gram-negative bacteria. An integrated approach encompassing structure-based drug design, organic synthesis and microbiology has been used to design, synthesise and biologically evaluate 33 oxazolidinone variants. A two-part strategy to potentiating oxazolidinone derivatives against E. coli was taken which involved improving predicted target-binding and enhancing the rate of compound ingress into the E. coli bacterium. It was hypothesised that oxazolidinones demonstrating substantial increases in either of these areas may minimise the detrimental impact on antibacterial activity caused by the efflux transporter AcrAB-TolC in E. coli. A structure-guided approach using in silico docking methods did not produce oxazolidinone derivatives with improved antibacterial activity against E. coli in this study. Attempts to increase E. coli activity by equipping compound libraries with ionisable nitrogen moieties whilst retaining a ribosomal-binding moiety at the C-5 oxazolidinone position proved to be a more successful strategy. A linezolid variant 10 featuring a piperazine in replacement for a morpholine ring, demonstrated an 8-fold increase in anti-E. coli activity over linezolid. Two compounds from a class termed ‘bis-oxazolidinones’, 69 and 72, exhibited on-target increases in anti-E. coli activity by 4- and 8 to 16-fold respectively, when compared to linezolid. Therefore, these findings demonstrate that it is possible to improve the anti-Gram-negative activity of the oxazolidinone class to encompass E. coli.
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Paula-Eduardo, Laila Facin de 1984. "Isolamento e identificação de compostos bioativos da geoprópolis (Melipona scutellaris) bioguiado pelo efeito antimicrobiano = Isolation and identification of bioactive compounds of geopropolis (Melipona scutellaris) bioguided by the antimicrobial effect." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/288513.
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Orientadores: Pedro Luiz Rosalen, Cínthia Pereira Machado Tabchoury<br>Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba<br>Made available in DSpace on 2018-08-26T11:28:01Z (GMT). No. of bitstreams: 1
Paula-Eduardo_LailaFacinde_M.pdf: 1396217 bytes, checksum: ee32ae3fccb5fc73fe047b8152a78b6e (MD5)
Previous issue date: 2014<br>Resumo: Os produtos naturais, comprovadamente, têm sido uma fonte promissora para descoberta de novos compostos bioativos. Dentre eles, a própolis coletada por abelhas Apis mellifera possui atividades biológicas descritas na literatura como anticárie, antibacteriana, anti-inflamatória, entre outras. Entretanto, a maioria dos estudos sobre própolis se refere àquelas coletadas por A. mellifera e pouco se tem conhecimento de outras, como a geoprópolis, produzida por abelhas sem ferrão do gênero Melipona. Em estudos recentes, a geoprópolis apresentou promissoras atividades antimicrobiana e anti-inflamatória, porém estas pesquisas ainda não evidenciaram quais as substâncias responsáveis por tais ações biológicas, especialmente contra o biofilme oral cariogênico. Portanto, o objetivo desse trabalho foi isolar e identificar o composto ativo da geoprópolis de Melipona scutellaris com atividade contra biofilme formado por Streptococcus mutans. Este objetivo foi alcançado por meio das seguintes metodologias: 1- fracionamento bioguiado do extrato etanólico da geoprópolis (EEGP); 2- isolamento e identificação do composto ativo; 3- avaliação do potencial anticárie do composto ativo utilizando modelo in vitro de inibição de biofilme oral monoespécie. Como resultado do fracionamento bioguiado foi isolado e identificado o composto nemorosona (C33H42O4, MM= 502 g/mol), uma benzofenona prenilada. A concentração inibitória mínima da nemorosona foi de 6,25 ¿ 12,5 ?g/mL e na concentração de 100 ?g/mL foi capaz de inibir em 95% a aderência do S. mutans em biofilme formado em microplacas de fundo côncavo. Em biofilme formado em discos de hidroxiapatita, a nemorosona na concentração 250 ?g/mL (0,50 mM) reduziu 65 % do peso seco, mais de 70% dos polissacarídeos e 48% da quantidade proteica além de diminuir a viabilidade bacteriana, quando comparada com o controle negativo (veículo, p<0,05). Estes resultados não diferiram estatisticamente da clorexidina a 0,12% (1,33 mM) (p>0,05). Portanto, concluímos que a nemorosona é um composto ativo isolado e identificado da geoprópolis com atividade antibiofilme de S. mutans com capacidade de alterar a composição bioquímica da matriz do biofilme de S. mutans, o que torna este composto promissor agente químico para o controle do biofilme oral<br>Abstract: Natural products have been demonstrated a promising source to discover new bioactive compounds. Among then, the propolis collected by Apis mellifera bees has biological activity described in the literature as anticairies, antimicrobial, anti-inflammatory, besides other activities. However, most of the studies on propolis refer to those collected by A. mellifera and little is known about others as geopropolis, which is collected by stingless bees of the genus Melipona. In recent studies, geopropolis presented promising antimicrobial and anti-inflammatory activities, but these studies have not revealed which is (are) the substance(s) responsible(s) for such biological activities, especially against the cariogenic oral biofilms. Therefore, the objective of this study was to isolate and identify the active compound from Melipona scutellaris geopropolis, which has activity against the biofilm formation by Streptococcus mutans. This goal was achieved by the following methodologies: 1- bioassay-guided fractionation of the goeporpolis ethanolic extract (EEGP); 2- isolation and identification of the active compound; 3- anticarie potential assessment of the active compound using an in vitro model of inhibition of the oral mono-species biofilm. As result of the bioassay-guided fractionation, the poliprenil benzophenone compound named nemorosone (C33H42O4, MW=502 g/mol) was isolated and identified. The nemorosone¿s minimum inhibitory concentration (MIC) was 6.25 ¿ 12.5 ?g/mL and the concentration of 100 ?g/mL was capable to inhibit by 95% the adherence of S. mutans¿s biofilm formed in U-bottom microtiter plates. In biofilm formed in hydroxyapatite disks, the nemorosone concentration of 250 ?g/mL (0.5 mM) reduced 65% of the dry weight, more than 70% of the polysaccharides and 48% of the protein content. In addition, it reduced the bacterial viability when compared to negative control (vehicle, p<0.05). These results did not differ statistically from chlorhexidine 0.12% (1.33 mM) (p> 0.05). Therefore, the conclusion is that nemorosone is the active compound isolated and identified from geopropolis with antibiofilm activity that is able to alter the biochemical composition of the S. mutans biofilm matrix, it makes this chemical compound promising to oral biofilm control<br>Mestrado<br>Farmacologia, Anestesiologia e Terapeutica<br>Mestra em Odontologia
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Riesbeck, Kristian. "Effects of fluoroquinolones on the immune system." Malmö : Dept. of Medical Microbiology, Lund University, Malmö General Hospital, 1994. http://books.google.com/books?id=-hRtAAAAMAAJ.
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Martini, Nataly Dominica. "The isolation and characterisation of antibacterial compounds from Combretum erythrophyllum (Burch.) Sond." Diss., Pretoria : [s.n.], 2001. http://upetd.up.ac.za/thesis/available/etd-07092002-153815/.
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Moro, Whitney Beysselance. "The design and synthesis of antibacterial inhibitors of NAD synthetase." Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2009r/moro.pdf.
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Thesis (Ph. D.)--University of Alabama at Birmingham, 2007.<br>Title from PDF title page (viewed Feb. 4, 2010). Additional advisors: Subramaniam Ananthan, David E. Graves, Craig D. Smith, Sadanandan E. Velu. Includes bibliographical references.
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Lo, Shiu-hong. "Antibacterial activity of some marine planktonic algae in Hong Kong /." Hong Kong : University of Hong Kong, 1996. http://sunzi.lib.hku.hk/hkuto/record.jsp?B19667152.
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Sitnikov, Dmitri. "Toxicity and adsorbance abilities of Alcell lignin to bacteria." Thesis, McGill University, 1999. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=29807.
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AlcellRTMlignin has been used commercially in adhesive preparation and brake pad linings and experimentally in animal feeds to reduce or eliminate diarrheal attacks in farm animals. Our study dealt with elucidating the antibacterial effect of AlcellRTMlignin. It would appear that adsorbance of E. coli cells to AlcellRTMlignin particles is not essential for destruction of the organism.<br>The antibacterial activity was delayed by the inclusion of Mg 2+ ions in the AlcellRTMlignin filtrate or in the enumeration medium (BHIA). Addition of bile salts to the enumeration medium (BHIA) enhanced the culturability loss of E. coli cells suspended in the filtrate of AlcellRTMlignin. Using FTIR methodology, it appears, that compounds of AlcellRTMlignin affect phospholipid-phospholipid and/or phospholipid-protein interactions in bacterial membranes, causing the patching of membrane phospholipids and proteins.<br>Additional studies are necessary to evaluate interactions of compounds of AlcellRTMlignin with bacterial cells.
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Messina, Maria Cipolla 1961. "The effect of liquid smoke on Listeria monocytogenes." Thesis, The University of Arizona, 1988. http://hdl.handle.net/10150/276677.
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Four strains of Listeria monocytogenes (LCDC 81-861, ATCC 19115, M1 and M2) examined in pure culture behaved similarly when exposed to a concentration of 0.5% CharSol C-10 liquid smoke by reducing Listeria numbers to an undetectable level within 4 hours post treatment. However, at the lower concentration of 0.25% liquid smoke, differences in resistance to the antimicrobial properties of smoke components become evident among these strains indicating that a level of 0.5% liquid smoke is more effective in controlling this organism. CharSol C-10 liquid smoke was used as a full strength dip treatment for beef franks surface inoculated with six strains of L. monocytogenes (LCDC 81-861, ATCC 19115, M1, M2, M5, and C6) then vacuum packaged and stored at 4 ± 1°C for 72 hours. Beef franks dipped in CharSol C-10 liquid smoke exhibited a significant (P < 0.001) reduction in L. monocytogenes numbers after 72 hours of storage at both inoculum levels of 1 x 10³ cells/ml and 1 x 10⁵ cells/ml.