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.
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.
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