Mechanisms of Antibiotic Resistance and Pathogenesis in Acinetobacter baumannii

Abstract

Acinetobacter baumannii is a Gram-negative bacterium that is a growing problem in the hospital setting. In fact, A. baumannii accounts for up to 20 percent of infections in intensive care units worldwide. Rates of multidrug resistance are increasing rapidly with many A. baumannii strains resistant to virtually all antimicrobials. These facts have galvanized efforts aimed at elucidating the pathogenic mechanisms employed by A. baumannii in order to identify novel therapeutic targets. Toward this end, the work described herein defines several novel mechanisms for antibiotic resistance and pathogenesis in A. baumannii. This work demonstrates that A. baumannii is a highly adaptable pathogen that responds to signals within the hospital and host environments in order to modulate its antibiotic resistance and pathogenic phenotypes. These signals include physiologic concentrations of monovalent cations, as well as limitation of essential nutrient metals such as Mn and Zn. Moreover, this work elucidates critical host factors that aid in defense against A. baumannii including the contribution of nutrient metal sequestration by calprotectin to inhibition of A. baumannii growth in vitro and in vivo. Additionally, susceptibility to A. baumannii infection varies with respect to the circadian clock, and resistance to A. baumannii infection can be induced in mice by treatment with dominant negative transposon mutants of A. baumannii. Taken together, this work defines critical physiologic adaptations of A. baumannii to the hospital and host environments and elucidates host factors that determine susceptibility or resistance to A. baumannii infection.