Going to extremes: progress in exploring new environments for novel antibiotics

The discoveries of penicillin and streptomycin were pivotal for infection control with the knowledge subsequently being used to enable the discovery of many other antibiotics currently used in clinical practice. These valuable compounds are generally derived from mesophilic soil microorganisms, predominantly Streptomyces species. Unfortunately, problems with the replication of results suggested that this discovery strategy was no longer viable, motivating a switch to combinatorial chemistry in conjunction with existing screening programmes to derive new antimicrobials. However, the chemical space occupied by these synthetic products is vastly reduced compared to those of natural products. More recent approaches such as using artificial intelligence to ‘design’ synthetic ligands to dock with molecular targets suggest that chemical synthesis is still a promising option for discovery. It is important to employ diverse discovery strategies to combat the worrying increase in antimicrobial resistance (AMR). Here, we reconsider whether nature can supply innovative solutions to recalcitrant infections. Specifically, we assess progress in identifying novel antibiotic-producing organisms from extreme and unusual environments. Many of these organisms have adapted physiologies which often means they produce different repertoires of bioactive metabolites compared to their mesophilic counterparts, including antibiotics. In addition, we examine insights into the regulation of extremotolerant bacterial physiologies that can be harnessed to increase the production of clinically important antibiotics and stimulate the synthesis of new antibiotics in mesophilic microorganisms. Finally, we comment on the insights provided by combinatorial approaches to the treatment of infectious diseases that might enhance the efficacy of antibiotics and reduce the development of AMR

Nature, extent and correlates of bullying and assault in penal populations

The present thesis is a detailed examination of bullying behaviour in Young Offender Institutions and assaultive behaviour in adult prisons and Young Offender Institutions. An amalgam of methods of enquiry were used throughout, which comprised i) questionnaires, ii) structured interviews. Hi) focus groups, iv) standardised measures of personality, intelli^ce and social background, v) analysis of official discipline report records, vi) analysis ff official assault incident report records and vii) analysis of computerised prisoner records. This mixture of methods, known as 'triangulation', was adopted in an attempt to achieve a more reliable and valid representation of bullying and assaultive behaviour occurring within penal establishments. Information was obtained from a variety of subject groups, including convicted young offenders, young offenders on remand, convicted adult prisoners, adult prisoners on remand, prison officers, prisons management and specialist staff working in the prisons. Data were analysed by means of parametric and non-parametric statistical techniques. Seven cross-sectional studies were designed and conducted, the results of which are reported herein. The first five studies examined only Young Offender Institutions. Concerning young offenders, the levels of bullying ivere comparatively high when compared with studies done on analogous populations. Among young offenders, the most common types of bullying were similar to those shown in previous studies, such as taxing, threats and name calling. More staff in Young Offender Institutions perceived bullying as a problem both nationally and in their own establishment than did young offenders. While staff and young offenders had discordant opinions as to the levels and types of bullying taking place within Young Offender Institutions, they had concordant views as to the characteristics of 'bullies' and 'victims'. The types of bullying (i.e. covert and overt) varied considerably according to type of Young Offender Institution and type of young offender under study. The introduction of an anti-bullying initiative in one Young Offender Institution appeared to change the way bullying was manifested, as noted in the prison records, by reducing overt bullying behaviour and increasing more subversive and covert bullying. The remaining two studies in the thesis examined assault in both adult prisons and Young Offender Institutions. Results revealed that the typology of assaults in adult prisons and young offender establishments were dissimilar in important respects. In Young Offender Institutions the assaults on prisoners were more likely to be 'spontaneous' and result in less severe injury to the victim, whereas in adult prisons the assaults were more likely to be 'planned' and result in more severe injury to the victim. When looking at sub-groups within Scottish prisons and Young Offender Institutions using discriminant function analysis, victims of assaults on prisoners were distinguishable from both perpetrators of assaults on staff and perpetrators of assaults on other prisoners, using a range of social background factors. Victims of assault in adult prisons were more accurately identified (91% correctly identified, compared with 43% at 'chance') than victims in Young Offender Institutions (73% correctly identified, compared with 47% at 'chance'). The introduction of anti-bullying initiatives into young offender establishments, and in particular, how they might effect overt and covert bullying in contrasting^ ways, is reflected upon. Moreover, the importance of obtaining information from a variety of subject groups and an amalgam of data gathering techniques ts highlighted. The utility of using factors relating to an inmate's social background, personality and intelligence to predict involvement in bullying is discussed. Finally, the main findings from the thesis are discussed in relation to the relevant literature, practical implications for intervention and areas where future research may be necessary

Conformational control of anticancer activity: the application of arene-linked dinuclear ruthenium(II) organometallics

Dinuclear metal complexes have emerged as a promising class of biologically active compounds which possess unique anticancer activity. Here, we describe a novel series of arene-linked dinuclear organometallic Ru(II) complexes, where the relative conformation of the ruthenium centres is controlled by the stereochemical configuration of 1,2-diphenylethylenediamine linker moieties, as confirmed by X-ray crystallography. The reactivity and cytotoxicity of these compounds is compared to flexible dinuclear and mononuclear analogues, demonstrating in all cases the complexes can undergo aquation, coordinate to typical biological donor ligands and importantly, in the case of dinuclear analogues, crosslink oligonucleotide and peptide sequences. Differences in the conformation of the isomeric dinuclear compounds lead to significantly different levels of cytotoxicity against A2780, A2780cisR and HEK-293 cell lines; isomers with a closed conformation are significantly more cytotoxic than isomers with a more open conformation and they are also significantly less susceptible to acquired resistance mechanisms operating in the A2780cisR cell line. These rigid dinuclear compounds possess markedly increased cytotoxicity relative to the non-cytotoxic mononuclear analogues that does not appear to be related to differences in complex lipophilicity or cellular uptake, which, in general, remain similar in magnitude across the series. Thus, the molecular conformation of such dinuclear species may be crucial in determining the nature of the adducts formed on coordination to biological targets in a cellular environment, and opens up a novel route toward the development of more active metal-based anticancer agents

Potential of cycloaddition reactions to generate cytotoxic metal drugs in vitro

Severe general toxicity issues blight many chemotherapeutics utilized in the treatment of cancers, resulting in the need for more selective drugs able to exert their biological activity at only the required location(s). Toward this aim, we report the development of an organometallic ruthenium compound, functionalized through a η6-bound arene ligand with a bicyclononyne derivative, able to participate in strain-promoted cycloaddition reactions with tetrazines. We show that combination of the ruthenium compound with a ditetrazine in biological media results in the in situ formation of a dinuclear molecule that is more cytotoxic toward cancer cells than the starting mononuclear ruthenium compound and tetrazine components. Such an approach may be extended to in vivo applications to construct a cytotoxic metallodrug at a tumor site, providing a novel approach toward the turn-on cytotoxicity of metallodrugs in the treatment of cancer

Overview of paratransgenesis as a strategy to control pathogen transmission by insect vectors

This article presents an overview of paratransgenesis as a strategy to control pathogen transmission by insect vectors. It first briefly summarises some of the disease-causing pathogens vectored by insects and emphasises the need for innovative control methods to counter the threat of resistance by both the vector insect to pesticides and the pathogens to therapeutic drugs. Subsequently, the state of art of paratransgenesis is described, which is a particularly ingenious method currently under development in many important vector insects that could provide an additional powerful tool for use in integrated pest control programmes. The requirements and recent advances of the paratransgenesis technique are detailed and an overview is given of the microorganisms selected for genetic modification, the effector molecules to be expressed and the environmental spread of the transgenic bacteria into wild insect populations. The results of experimental models of paratransgenesis developed with triatomines, mosquitoes, sandflies and tsetse flies are analysed. Finally, the regulatory and safety rules to be satisfied for the successful environmental release of the genetically engineered organisms produced in paratransgenesis are considered