Following the expiry of patent protection of the innovator product Berenil®, there has been an influx of substandard generic substitutes of the veterinary trypanocide in international commerce, which have been implicated as being a major contributor to the emergence of drug resistance. This situation has necessitated the development of analytical techniques, which would help safeguard the quality and efficacy of generic formulations of diminazene. A selective, accurate, precise and simple reverse-phase isocratic HPLC method for the simultaneous assay of diminazene aceturate and antipyrine (excipient) in pharmaceutical formulations has been developed and validated. The degradation and manufacturing impurities of diminazene have been identified by electrospray ionization mass spectrometry and characterized by NMR spectroscopy of the synthetic compounds. The developed method has been applied for the quality evaluation of over one hundred generic samples of diminazene obtained from Sub -Saharan Africa. The results give an indication that the quality of generic formulations of diminazene on the African market is compromised. Changes in the metabolism of a drug can lead to altered pharmacokinetics, resulting in an increase or decrease in drug plasma concentration, leading to toxification or therapeutic failure. The metabolism of diminazene and pentamidine in isolated rat and pig hepatocytes have been investigated. Diminazene was not metabolized in either rat or pig hepatocytes. While there were no obvious qualitative differences in the metabolic profiles of pentamidine in either of the animals, the rate of metabolism in rats appeared to be faster. Pretreatment of rats with either 3-methylcholanthrene (3-MC), phenobarbitone (PB) or deltamethrin (DM) caused inhibition of pentamidine metabolism to different extents. There were significant differences between the profiles of the three major metabolites of pentamidine in DM and 3-MC pretreated rats compared to the control group, whereas etreatment with PB did not result in any significant changes in profiles of metabolites.

No description available.

The evolution of antibiotic resistance presents an escalating problem in the treatment of various infectious diseases worldwide. Although the origin of antibiotic resistance genes is not generally clearly documented, it has been thought that they evolved from specific genetic elements which eventually managed to spread to other microorganism of different strains and species through mobile genetics elements, transposons and plasmids. Extensively studying all aspects of these genes and their impact on the development of new treatments and drugs is of extreme importance. This study focuses on evolving and understanding how novel antibiotic resistance develops. Error prone PCR (EP-PCR) was used to introduce random mutation in an arr gene which confers high level resistance to rifampicin in E. coli. The clones obtained from EP-PCR were screened on different antibiotics with varying concentration in an attempt to isolate a clone with an increased minimum inhibitory concentration (MIC) as compared to the wild type parent strain (pBstN49). Several clones showed decreased levels of resistance against rifampicin but however none showed any significant increase in any of the other antibiotic MICs tested.

Degree of Master of Science in Medicine by Research Only Dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science in Medicine by Research. Johannesburg, 2012 / Genetic heterogeneity of Mycobacterium tuberculosis demonstrating mixed infections or affecting single strains has been previously described. A single sputum culture from five patients with drug-resistant tuberculosis treated at Sizwe Hospital was analysed in-depth for genotypic and phenotypic heterogeneity. IS6110-based restriction fragment length polymorphism (RFLP) was performed on 20 colonies from each sputum for detection of mixed infections and clonal heterogeneity. No mixed infections were found, but IS6110-RFLP-linked clonal heterogeneity was observed in one patient. Drug susceptibility testing (DST) and sequencing of nine drug-resistance-associated genes performed on a total of 99 colonies from the five patients failed to show genotypic hetero-resistance. On DST, however, discordant rifampicin resistance findings were encountered in one patient. Minimal inhibitory concentrations performed on these colonies were close to the rifampicin critical concentration used for resistance determination, suggesting failure of the BACTEC MGIT 960 assay to reliably determine rifampicin susceptibility in strains with borderline resistance.

by Lai-chu Wu. / Bibliography: leaves 212-241 / Thesis (M.Ph.)--Chinese University of Hong Kong, 1984

Hospital-acquired infections are the most frequent adverse event in healthcare delivery worldwide. Seven in ten hospital-acquired infections exhibit resistance to at least one antibiotic, and three in five doctors have encountered an infection unresponsive to any treatment at all. This prolongs hospitalisation, increases suffering, and causes long-term disability and unnecessary death. At present the antibiotic pipeline is unable to meet the demand for novel antibiotics needed to treat these infections. Herein I discuss how the lack of new scaffolds, limitations of target-based screening, and poor target validation each contribute to the current bottleneck in the antibiotic pipeline. In turn, I argue that the development and application of chemical probes is a more fruitful way to make progress towards new antibiotics with novel mechanisms of action. This dissertation describes a combined chemical-biology study in the search for novel inhibitors of the human pathogens Pseudomonas aeruginosa and Staphylococcus aureus. First we extend organocatalysis to the field of diversity-oriented synthesis as a powerful means to generate molecular diversity and complexity in small molecule screening collections. We then study a family of potential biofilm inhibitors identified from a diverse screening collection, and for which we suggest a possible mode of action upon the quorum sensing receptors LasR and RhlR. Thereafter we provide evidence that a novel macrocycle, based upon the cylindrocyclophane family of natural products, inhibits methicillin-resistant S. aureus through action upon the respiratory chain. Finally, we also report insights into the structure and small molecule inhibition of a key P. aeruginosa drug target, malate synthase G. Together the findings in this dissertation encourage the development and application of divergent synthesis and unbiased screening methods in antibacterial discovery.

by Li Yanchun. / "August 2000." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (p. 193-213). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

archives@tulane.edu / 1 / Brittany J Dodson

The primary aim of this thesis was to synthesize a new class of peptide mimics derived from N-acylisatins and to investigate various methodologies for their synthesis. N-Acetylisatin 15 and its derivatives 39 and 40 were found to undergo facile nucleophilic ring-opening with amino acid esters yielding a range of 2-acetamidophenylglyoxylamide derivatives in moderate to good yields. This type of reaction was also found to work for di- and tripeptide methyl ester hydrochlorides leading to a range of N-glyoxylamide peptide mimics. The methodology of the reaction conditions was further extended to N,N′-oxalyl bisisatins 17 and 134, and 1,3,5-tris(2,3-dioxoindoline-1-carbonyl)benzene 168 substrates and their reaction with amino acid esters gave a new range of C,C′-linked-bis-glyoxylamide peptide mimics and C,C′,C′′-linked tris-glyoxylamide peptide mimics respectively. Meanwhile, reactions of N-acylisatins with 1,10-diaminodecane 155 and tris(2-aminoethyl)amine 167 gave the corresponding bis and tris-glyoxylamides. In the event of introducing amino acids at the N-1 position of isatin 9, a range of NH protecting groups for the synthesis of N-protected amino acid acyl isatins 193 were examined. It was found that the phthalamido group, e.g. phthaloylglycine 197, was the best protecting group for the introduction of a glycine unit at the N-1 position of isatin 9. Additionally, a viable and interesting alternative approach utilizing N-succinyl acylisatin 158 as the starting material was also demonstrated. In continuation of our interest in the peptidomimetic approach, a new class of cyclic peptide mimics using Grubbs?? ring-closing metathesis approach was also successfully synthesized. A range of bis-O-allyl substrates 237, 240, 242 and 246 were prepared from reaction of the corresponding N-acylisatins with L-valine allyl ester hydrochloride 236 and 1,10- diaminodecane 155 respectively. High conversion yields of the target macrocyclic systems 238, 241 and 243 were observed when the bis-Oallyl substrates were irradiated with Hoveyda-Grubb catalyst in a microwave reactor. These latter studies will provide a synthetically versatile platform for the future design of potential new drugs candidates against Gram-positive bacterial infections

Thesis (Honors)--Liberty University Honors Program, 2008. / Includes bibliographical references.