Acinetobacter baumannii can use multiple siderophores for iron acquisition, but only acinetobactin is required for virulence

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.

Author summary

Acinetobacter baumannii is an emerging pathogen that is gaining notoriety as a major global health threat due to its extensive drug resistance. Accordingly, 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 a priority “critical” pathogen. Unfortunately, little is known about how A. baumannii causes infection. Iron is an essential nutrient to almost all forms of life and plays a key role in shaping host-pathogen interactions. A. baumannii secretes multiple low molecular weight iron chelators (siderophores) to help fulfill its need for the metal. Here we demonstrate that one of these siderophores, acinetobactin, is required for growth using host iron sources, whilst two others (baumannoferrin and fimsbactins) are dispensable to this function. Although 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.