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Mobility and detection of antimicrobial resistance genes in Mycoplasma hominis, Ureaplasma parvum, Ureaplasma urealyticum and Neisseria gonorrhoeae

Sharratt, Martin 2023. Mobility and detection of antimicrobial resistance genes in Mycoplasma hominis, Ureaplasma parvum, Ureaplasma urealyticum and Neisseria gonorrhoeae. PhD Thesis, Cardiff University.
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Mycoplasmas are some of the most structurally minimalist bacteria currently known to science. As urogenital pathogens, they can lead to a variety of adverse outcomes such as spontaneous abortion, pre-term birth and neonatal pneumonia. Their structural simplicity means that they lack most of the targets of antibiotic treatments, and their high degree of genomic plasticity allows them to rapidly adapt to the few treatments that are available. As such, the primary goal of this work was to investigate the mechanisms and detection of tetracycline and quinolone resistance in Mycoplasma hominis as well as tetracycline resistance in Ureaplasma parvum and Ureaplasma urealyticum. In addition, I investigated the effectiveness of utilizing real-time PCR techniques for the clinical detection of urogenital mycoplasmas and their associated antimicrobial resistances, along with that of Neisseria gonorrhoea and Mycoplasma genitalium due to their international prominence as “superbugs”. An interrogation of the mechanisms behind fluoroquinolone resistance in M. hominis demonstrated an environmentally driven mechanism of resistance, mediated by mutations I observed in gyrA that preceded mutations in the complementary parC gene. Furthermore, I observed a similarly high degree of genomic heterogenicity between the tetM genes that mediate tetracycline resistance in M. hominis, suggesting that horizontal gene transfer mediated the development of tetracycline resistance in M. hominis. These observations were only partially mirrored in my analysis of tetracycline resistant Ureaplasma spp. All Ureaplasma urealyticum isolates shared a common insertion site for tetM that appeared to be part of a Tn916-carried composite integrated conjugal element (ICE), while most U. parvum isolates retained a second conserved tetM insertion site (but without most of the expected Tn916-associated genes) and a final U. parvum isolate that appears to have acquired a Tn916 insertion event at a unique third somatic position. For all Mollicutes, the transition from standard bacterial coding where UGA is stop, and not the main histidine codon, appears to drive mutation in these open-reading frames in M. hominis and Ureaplasma spp. Analysing isolates collected as part of the Antibiotic Guardian study, which had to be significantly truncated due to the COVID-19 outbreak and restrictions on sexual health patients coming into hospital, found that U. parvum had highest prevalence, followed by M hominis, U. urealyticum, N. gonorrhoea and finally M. genitalium. Furthermore, a significantly higher prevalence of U. parvum and M. hominis in female patients suggested a gender bias for pathogenicity. The in-house qPCR assays used showed 100% concordance with both commercial molecular methods and NHS culture methods for detection of urogenital mycoplasmas, indicating the reliability and accuracy of this assay for use as a rapid diagnostic tool. Furthermore, the high levels of resistance in N. gonorrhoea, M. genitalium and M. hominis observed were identical between SpeeDx commercial assays (not M. hominis) and culture-based confirmation. However, the significantly lower viability of N. gonorrhoea in culture demonstrated that the molecular methods had a distinctive advantage in diagnosis relative to traditional susceptibility testing methods. Given the increasing prevalence of resistance for all pathogens, continued surveillance to monitor antimicrobial resistance trends is required.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 23 January 2024
Last Modified: 23 Jan 2024 16:25

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