Auxiliary factors: a chink in the armor of MRSA resistance to β-lactam antibiotics

Combination agents provide an important orthogonal approach to treat infectious diseases, particularly those caused by drug resistant pathogens. Indeed, applying a biologically 'rational' and systems-level paradigm to discover potent, selective, and synergistic agents would augment current (and arguably overly relied upon) empirical and serendipitous approaches to such discovery efforts. Here, we review the cellular mechanisms of β-lactam drug resistance and tolerance achieved amongst methicillin-resistant Staphylococcus aureus (MRSA) as well as their molecular targets and strategies to identify cognate inhibitors as potential combination agents to restore β-lactam efficacy against MRSA.