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The potassium efflux systems KefB and KefC may be targets for novel antibiotics. The <I>kefC</I> gene has been cloned and molecular analysis on the KefC protein has begun. The <I>yabF</I> gene, which lies directly upstream of the <I>kefC</I> gene on the <I>E. coli </I>chromosome, is required for KefC activity. The aims of the project were to characterise the physiological role of KefB, to clone the <I>KefB</I> gene, and to initiate molecular studies on the regulation of KefB activity. In the course of these studies, it has been shown that; 1. KefB and KefC do not afford protection against all electrophiles since they do not afford protection against the electrophile iodoacetate; 2. KefB and KefC can be partially activated by electrophiles, without the formation of a glutathione-adduct. However, complete activation of KefB and KefC requires the formation of a glutathione-adduct; 3. There may be more than one site for direct activation of KefB and KefC; a periplasmic and a cytoplasmic site; 4. The KefB protein is homologous to the KefC protein, the amino-terminal domain spans the membrane between six and twelve times and the carboxy-terminal domain is cytoplasmic; 5. KefB, for full activation, requires the ancillary protein YhaH, a YabF homologue. YhaH and YabF are involved in the regulation of KefB (and possibly KefC), but, for activation, each is specific for its own system, i.e. only YhaH activates KefB and only YabF activates KefC. Based upon this work, an updated model for the different states of KefB and KefC has been proposed, the involvement of the YhaH and YabF proteins are discussed and molecular studies on KefB have been initiated.

This thesis describes investigations made into the chemistry of C-4 substituted glutarimides. It develops two contrasting approaches to this goal, which reflect the previous synthetic interests in the area. The glutarimides made were screened for potential agrochemical actions at Shell Research Centre, Sittingbourne. The anti-Leukemia alkaloid sesbanimide has prompted much recent work into the formation of glutarimides attached to functionalised precursors. This chemistry was developed by the formation of a glutarimide from C-5 of xylodialdofuranose, using standard methods. Wittig extension of the aldehyde, followed by Michael addition of malonate and dealkoxycarbonylation gave a glutarate diester, this was converted to the glutarimide via an anhydride. A glutarimide was similarly constructed from a β-ribose residue, forming an analogue of the β-C-nucleosides. An approach to the epimeric α- ribo-glutarimide was also made. The α- and β-riboaldehydes, from which the glutarimides were elaborated, were each formed stereospecifically by the ring contractions of a pyranose triflate. Synthetic interest towards the so-called glutarimide antibiotics has centred around the elaboration of a side chain attached to a pre-formed glutarimide. The common precursors in this work were glutarimides attached via C-4 to β-acetyl functions. The corresponding side chain in this work was activated, in a novel manner, by the formation of a stabilized ylid at that centre. Wittig reactions between this ylid and a number of carbonyl compounds were achieved. Some of these Wittig products were elaborated further, a number of simple heterocycles were thus formed, attached to glutarimide via a 1-carbon extension. Using a carbohydrate derived side chain an attempt to form a glutarimide attached to a shikimate-related residue was made, by means of an intramolecular aldol cyclisation. An N-substituted glutarimide was formed in a novel reaction between an iminophosphorane and glutaric anhydride. Many of these synthetic glutarimides exhibited some biological activity.

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Microbial keratitis is a major cause of avoidable visual impairment worldwide with S. aureus a leading cause of this disease in humans. Recently S. aureus isolated from eye infections have exhibited resistance to many antibiotics with those isolates from more severe infections exhibiting higher rates of antibiotic resistance. New therapies are therefore needed to ensure adequate treatment for these infections. In microbial keratitis the hosts' immune response is responsible for significant disease pathology so development of a therapy which also targets the immune response would be beneficial. The fimbrolides produced by Delisea pulchra are potential candidates as they are both growth inhibitory and immunomodulatory in vitro. The antibiotic susceptibility of clinical S. aureus isolates from ocular infections was determined using the CDS method and similarity of these isolates determined by PFGE and PCR-ribotyping. In addition the effect of fimbrolides on bacterial growth alone or in combination with antibiotics and the immune response to bacterial stimulation in PMNs and HCE cells was determined. Fimbrolides were then topically applied to S. aureus corneal infections and the effect of these compounds on disease progression determined by assessing corneal pathology, bacterial numbers and PMNs recovered from infected corneas. A larger proportion of keratitis isolates exhibited resistance to antibiotics than conjunctivitis isolates. Keratitis isolates were also related within a geographical region. The fimbrolides inhibited bacterial growth and modulated the immune response to bacterial stimulation in vitro. These compounds also exhibited synergy with conventional antimicrobials. In combination with ciprofloxacin the fimbrolides reduced the clinical score and numbers of bacteria recovered from ciprofloxacin-resistant or ciprofloxacin-sensitive S. aureus corneal infections. This thesis has identified that S. aureus isolates which produce the worst disease pathology in the eye are related and also exhibit higher rates of resistance to antibiotics indicating novel therapies to treat these infections are needed. This thesis demonstrated that fimbrolides inhibit S. aureus growth, exhibit synergy with antibiotics and modulate the immune response in vitro. In combination with ciprofloxacin the fimbrolides also improved disease pathology in keratitis, illustrating the potential of fimbrolides to be used as an adjunct therapy in the treatment of S. aureus keratitis.

x, 133 leaves : ill., bibliog. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Microbiology, 1972

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2001. / Härtill 5 uppsatser.