Acinetobacter baumannii is a prominent multidrug resistant pathogen responsible for major disease burden worldwide. A. baumannii causes a wide range of infections, with bacteraemia and pneumonia being most commonly associated with poor health outcomes and death (Wong et al., 2017). The ability of the bacterium to colonise, survive and thrive within hospital environments has been well- documented. The causative mechanisms, including biofilm formation, antimicrobial resistance and tolerance to desiccation, have been extensively studied over the last decade (Giles et al., 2015, Harding et al., 2018). In contrast, the behaviour of A. baumannii during disease and how it overcomes clearance by the immune system remains poorly understood. An important factor to their success during infection, is the ability to maintain cellular metal ion homeostasis when encountering the plethora of host-defence mechanisms. In a series of key publications, we have shown that metal ions, and in particular zinc, play an important role in the immune-mediated restriction of bacterial proliferation (Eijkelkamp et al., 2011b, Plumptre et al., 2014). Metal ion stress at the host-pathogen interface is mediated by a combination of starvation and intoxication strategies (Hood and Skaar, 2012). Despite this, how A. baumannii deals with switching between metal starvation and intoxication remains unknown. We have also shown that A. baumannii is highly susceptible to changes in the abundance of different metal combinations (Hassan et al., 2017), such as high zinc and high copper, or high zinc and low iron, which are conditions that can exist at the hostile host-pathogen interface.
In this proposal, we aim to comprehensively dissect the metal ion sensing and homeostatic mechanisms of A. baumannii. Our primary objective is to identify a weakness in the A. baumannii metalloregulatory network that can be exploited for novel treatment strategies. As host zinc plays a central role in preventing bacterial infections, we will investigate A. baumannii behaviour during zinc deficiency using a novel, multi-pronged in vitro and in vivo approach.