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Adjuvant therapies for mupirocin-resistant bacteria


Project Description

Multi-drug resistant Staphylococcus aureus has been able to adapt constantly to therapeutic use of antibiotics and remains an important source of clinical complications, morbidity and mortality. Mupirocin (pseudomonic acid) is a polyketide antibiotic, routinely used for nasal decolonisation with good results but also with high frequency or recurrence. This is largely the result of prevalence at 1-2% of a highly mupirocin-resistant sub-population of MRSA, which is tolerant at >1 g/L due to carriage of a plasmid-borne copy of a gene called mupA (Das, Anderson et al. 2012). Mupirocin inhibits protein synthesis by targeting the isoleucyl-tRNA synthetase IleS. High levels of resistance are observed in the presence of a variant, mupA-encoded sythetase, which has no affinity for mupirocin.

Antibiotic combinations and the use of adjuvants in therapy are considered at present as a very promising and mainstream approach to the management of bacterial infections. We hypothesise that reducing bacterial membrane integrity by co-application of antimicrobial peptide nisin enhances bacterial susceptibility to mupirocin. Our preliminary results confirm this hypothesis and reveal high synergy between mupirocin and nisin with mupirocin susceptibility at <0.5 MIC nisin, returning to that of a reference S. aureus (Oxford) isolate. We further hypothesise that loss of mupirocin resistance during adjuvant nisin treatment is the result of loss of mupA.

The University of Nottingham is one of the world’s most respected research-intensive universities, ranked 8th in the UK for research power (REF 2014). Students studying in the School of Life Sciences will have the opportunity to thrive in a vibrant, multidisciplinary environment, with expert supervision from leaders in their field, state-of-the-art facilities and strong links with industry. Students are closely monitored in terms of their personal and professional progression throughout their study period and are assigned academic mentors in addition to their supervisory team. The School provides structured training as a fundamental part of postgraduate personal development and our training programme enables students to develop skills across the four domains of the Vitae Researcher Development Framework (RDF). During their studies, students will also have the opportunity to attend and present at conferences around the world. The School puts strong emphasis on the promotion of postgraduate research with a 2-day annual PhD research symposium attended by all students, plus academic staff and invited speakers.

In this project we aim to investigate the level of resistance to mupirocin, bacterial susceptibility to antibiotic combinations and the use of membrane and cell wall-disrupting adjuvants. The molecular origins of mupirocin resistance will also be investigated and the ability to uptake/retain resistance-conferring plasmids will be characterised. Molecular modelling will be used to describe the structural origins of mupirocin action and structural analysis of IleS will be used for high-performance computational screening of potentially inhibitory compounds for target-driven drug development.

Funding Notes

Home applicants should contact the supervisor to determine the current funding status for this project. EU applicants should visit the Graduate School webpages for information on specific EU scholarships View Website. International applicants should visit our International Research Scholarships page for information regarding fees and funding at the University View Website.

References

1. Bonev, B. et al. (2008). Principles of assessing bacterial susceptibility to antibiotics using the agar diffusion method. J. Antimic. Chemother. 61(6): 1295-1301.
2. Das, S. et al. (2012). Association of Mupirocin Resistance (mupA) Gene and Presence of Antibiotic Resistance in Methicillin-Resistant Staphylococcus aureus (MRSA). J. Mol. Diagnostics 14(6): 680-680.
3. Hyde, A.J. et al. (2006). Nisin-induced changes in Bacillus morphology suggest a paradigm of antibiotic action. PNAS 103(52): 19896-19901.
4. Kuehne, S.A. et al. (2010). The role of toxin A and toxin B in Clostridium difficile infection. Nature 467(7316): 711-U797.
5. Okolie, C.E. et al. (2015). Development of a heptaplex PCR assay for identification of Staphylococcus aureus and CoNS with simultaneous detection of virulence and antibiotic resistance genes. BMC Microbiology 15.
6. Hook, A.L. et al. (2012) Combinatorial discovery of novel polymers resistant to bacterial attachment. Nature Biotechnol. 30: 868-875.
7. Kuehne S.A. (2014) The importance of toxin A, toxin B and CDT in virulence of an epidemic Clostridium difficile strain. J. Inf. Dis. 209:83-86.
8. Murray, E.J. (2014) Targeting Staphylococcus aureus quorum sensing with nonpeptidic small molecule inhibitors. J. Med. Chem. 57: 2813-9.

How good is research at University of Nottingham in Biological Sciences?

FTE Category A staff submitted: 90.86

Research output data provided by the Research Excellence Framework (REF)

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