The Global Transcription Response of Acinetobacter baumannii in the Presence of Gallium Protoporphyrin IX

Abstract

Acinetobacter baumannii is a bacterium identified as a serious threat to human health by the U.S. Centers for Disease Control and Prevention ( CDC ). A. baumannii has this designation because of its prevalence in hospitals and increased frequency of drug resistance worldwide. The CDC estimates 12,000 infections and 500 deaths are caused by A. baumannii every year in the United States. Exacerbating the lack of pharmaceutical options, the crucial mechanisms by which A. baumannii copes and interacts with human systems is uncertain, making drug development difficult. However, A. baumannii, like practically all other organisms, requires iron for critical enzymes involved in energy production, DNA synthesis, and detoxification. Many other human pathogens have elaborate systems to acquire heme or free iron from the host and environment. While ferric iron uptake systems have been described for A. baumannii, a heme utilization system has not been identified in this organism. However, studies have suggested a possible role of heme acquisition for A. baumannii. The first example describes the lysis of red blood cells by A. baumannii and the second reported the ability of gallium protoporphryin IX (GaPPIX), a molecule that is similar to the oxygen carrying heme found in our red blood cells, to kill multidrug-resistant A. baumannii. In spite of the ability of A. baumannii to produce heme endogenously, the susceptibility of A. baumannii to GaPPIX supports utilization of exogenous heme. Therefore, we hypothesized A. baumannii incorporates GaPPIX in a manner similar to the normal iron porphyrin ring leading to enzyme dysfunctions and cell death. In silico analyses performed on >2500 A. baumannii genomes from NCBI GenBank resulted in a subset of genes from the open pangenome of A. baumannii. Subsequent chokepoint analysis suggested points along the heme synthesis pathway as potential drug targets. Also, we studied the effects of GaPPIX usage on total metal concentrations and catalase activity. This work supports GaPPIX as an effective anti-A. baumannii compound that kills multidrug-resistant isolates. Additionally, the toxicity of GaPPIX is likely partially due to incorporation of GaPPIX into the catalase of A. baumannii. Overall, this work supports future investigations into the heme metabolism of A. baumannii for antimicrobial target identification.