Avenues to addressing A. baumannii infections

Antibiotics have been a one of the most revolutionary technologies to alter the course of human life expectancies. As a society, we have become accustomed to the reduced mortality antibiotics have afforded compared to even one century ago. For many years, new antibiotics coming into use kept pace with the steady evolution of bacterial drug resistance. This balance began to change as the challenge of finding new and effective antibiotics grew harder, and the economics of developing and deploying new antibiotics became prohibitively costly to private enterprises. Without the steady flow of new antibiotics that bacteria are susceptible to, antibiotic resistance has become an increasingly daunting problem in human healthcare. This has reached the point that pan drug resistant infections are no longer unheard of. These infections leave doctors scrambling for experimental treatments in hope of a cure. This is of particular concern among a set of bacteria that are referred to by the apt acronym ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.). These bacteria are common causes of antibiotic resistant infections that are community acquired and healthcare associated. The gram-positive pathogen S. aureus is associated with the largest number of antibiotic resistant infections annually. These occur as both community and healthcare associated. The gram-negative pathogen A. baumannii causes substantially fewer infections than S. aureus, and primarily presents as a healthcare associated. However, A. baumannii is often extensively antibiotic resistant or even pan drug resistant complicating infection treatment. A. baumannii is also easily transmitted among patients and is a common cause of infection outbreaks, especially in intensive care units (ICUs). Prevention is a crucial component to counter bacterial infections and is particularly important for managing the spread of antibiotic resistant bacteria. The CDC and the WHO both describe improved infection prevention as key to countering the health threat of antibiotic resistance, as well as preserving new antibiotics that are deployed in the clinic. This is due to the simple fact that if fewer people are infected by a pathogen there are fewer deaths from the disease, fewer antibiotics perscribed, and fewer opportunities for antibiotic resistance to arise.
In this dissertation, elements of A. baumannii infection control and prevention will be examined through three projects. In the first project, we investigated how A. baumannii, and bacteria more broadly, respond to quaternary amine disinfectants used to sanitize surfaces, hands, and equipment. In this work, we described a dual-action and concentration-dependent mechanism for benzalkonium chloride antibacterial activity. Our discovery extends to additional quaternary amine molecules and suggests ways that inadequate use of disinfectants may influence antibiotic tolerance. This study also identified a quaternary amine medication used for irritable bowel disease that could be repurposed as a broad-spectrum antibiotic. This observation suggests that quaternary amines may be useful molecular structures for designing new antimicrobials. The second study peered into the mechanisms by which A. baumannii asymptomatically colonizes patients with respect to the host microbiota. Here we found that in vitro, A. baumannii is capable of inhibiting commensal bacteria commonly found in the human nasal cavity and on the skin. We show that inhibition occurs in an iron-dependent manner and that iron starvation by the siderophore acinetobactin is likely the primary route by which A. baumannii inhibits commensal bacteria in vitro. The final project involved the development of single-domain antibodies that specifically bind A. baumannii. These proteins could potentially be used in diagnostics or as part of species specific therapeutics. Cumulatively, this body of work strives to identify multiple avenues for addressing the threat posed by A. baumannii to human health and wellbeing.