Abstract
Acinetobacter baumannii is an emerging pathogen that poses a global health threat due to a lack of therapeutic options for treating drug-resistant strains. In addition to acquiring resistance to last-resort antibiotics, the success of A. baumannii is partially due to its ability to effectively compete with the host for essential metals. Iron is fundamental in shaping host-pathogen interactions, where the host restricts availability of this nutrient in an effort to curtail bacterial proliferation. To circumvent restriction, pathogens possess numerous mechanisms to obtain iron, including through the use of iron-scavenging siderophores. A. baumannii elaborates up to ten distinct siderophores, encoded from three different loci: acinetobactin and pre-acinetobactin (collectively, acinetobactin), baumannoferrins A and B, and fimsbactins A-F. The expression of multiple siderophores is common amongst bacterial pathogens and often linked to virulence, yet the collective contribution of these siderophores to A. baumannii survival and pathogenesis has not been investigated. Here we begin dissecting functional redundancy in the siderophore-based iron acquisition pathways of A. baumannii. Excess iron inhibits overall siderophore production by the bacterium, and the siderophore-associated loci are uniformly upregulated during iron restriction in vitro and in vivo. Further, disrupting all of the siderophore biosynthetic pathways is necessary to drastically reduce total siderophore production by A. baumannii, together suggesting a high degree of functional redundancy between the metabolites. By contrast, inactivation of acinetobactin biosynthesis alone impairs growth on human serum, transferrin, and lactoferrin, and severely attenuates survival of A. baumannii in a murine bacteremia model. These results suggest that whilst A. baumannii synthesizes multiple iron chelators, acinetobactin is critical to supporting growth of the pathogen on host iron sources. Given the acinetobactin locus is highly conserved and required for virulence of A. baumannii, designing therapeutics targeting the biosynthesis and/or transport of this siderophore may represent an effective means of combating this pathogen.
Highlights
Acinetobacter baumannii is an opportunistic pathogen that is capable of causing a wide variety of diseases ranging from burn, wound, and urinary tract infections to more serious conditions such as ventilator-associated pneumonia and sepsis [1]
All three siderophores are expressed under iron-restriction and in the infected host, disrupting acinetobactin production alone severely attenuates the survival of A. baumannii in a mouse model of bacteremia
Given the high degree of conservation of acinetobactin in Acinetobacter spp., and its essentiality to virulence, we propose that targeting production or uptake of this siderophore represents an attractive option for the development of novel therapeutics
Summary
Acinetobacter baumannii is an opportunistic pathogen that is capable of causing a wide variety of diseases ranging from burn, wound, and urinary tract infections to more serious conditions such as ventilator-associated pneumonia and sepsis [1]. The World Health Organization has placed A. baumannii at the top of its list of bacteria urgently requiring research and development into novel therapeutic approaches, designating it as a priority “critical” pathogen [9]. Host mechanisms of iron-withholding include maintaining it in complex with heme in hemoproteins, reducing ferroportin expression to limit its release from macrophages, and sequestering it within glycoproteins such as transferrin and lactoferrin, found predominantly in the Acinetobactin is required for Acinetobacter baumannii pathogenicity blood and bodily secretions, respectively [27]. As such, accessing iron is perhaps one of the most formidable challenges faced by invading pathogens and is required for replication within the host
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