Molecular Mechanisms Underlying Resistance to Clinical Combination Therapy in <i>Acinetobacter baumannii</i>

<p>Nosocomial <em>A. baumannii </em>infections are a rising problem globally. Remarkable genome plasticity facilitates the rapid acquisition of resistance determinants and swift adaptation to new antibiotic therapies. Clinical <em>A. baumannii </em>frequently possess an impressively MDR phenotype, which can make it extremely difficult to treat with anything but our last line therapies. In the absence of new therapeutics, combination therapy has many advantages that make it extremely enticing for sustainably treating drug resistant <em>A. baumannii</em>. These include exploiting synergy, lowering dosages to minimise side effects, revitalising our existing drugs; and broadened antimicrobial targeting. Concerningly, despite its widespread application, very little is known about how resistance develops in response to combination therapy. One combination that is commonly used in Australian hospitals is trimethoprim and sulfamethoxazole. The aim of this project was to identify genes involved in resistance to this combination in two strains of <em>A. baumannii; </em>the reference strain ATCC 17978 and a clinical strain BAL062. Two complementary sequence-based approaches were employed; Directed Evolution and Transposon Directed Insertion Site Sequencing (TraDIS). These techniques identified a range expected resistance genes (e.g. RND efflux component and regulator genes) as well as some interesting novel resistance determinants.</p>