In-Depth Analysis of the Role of the Acinetobactin Cluster in the Virulence of Acinetobacter baumannii

Abstract

Acinetobacter baumannii is a multidrug-resistant pathogen that represents a serious threat to global health. A. baumannii possesses a wide range of virulence factors that contribute to the bacterial pathogenicity. Among them, the siderophore acinetobactin is one of the most important, being essential for the development of the infection. In this study we performed an in-depth analysis of the acinetobactin cluster in the strain A. baumannii ATCC 17978. For this purpose, nineteen individual isogenic mutant strains were generated, and further phenotypical analysis were performed. Individual mutants lacking the biosynthetic genes entA, basG, basC, basD, and basB showed a significant loss in virulence, due to the disruption in the acinetobactin production. Similarly, the gene bauA, coding for the acinetobactin receptor, was also found to be crucial for the bacterial pathogenesis. In addition, the analysis of the ΔbasJ/ΔfbsB double mutant strain demonstrated the high level of genetic redundancy between siderophores where the role of specific genes of the acinetobactin cluster can be fulfilled by their fimsbactin redundant genes. Overall, this study highlights the essential role of entA, basG, basC, basD, basB and bauA in the pathogenicity of A. baumannii and provides potential therapeutic targets for the design of new antivirulence agents against this microorganism.

Hybrid antigens expressing surface loops of BauA from Acinetobacter baumannii are capable of inducing protection against infection

“…BauA has the typical outer-membrane TonB dependent transporter (TBDT) architecture with a ß-barrel formed by 22 anti-parallel beta-strands and a plug domain folded inside of the barrel. Complementing studies demonstrating the importance of acinetobactin synthesis in virulence in mouse infection models ( 14 , 16 ) and the observation that deletion of BauA also leads to reduced virulence ( 16 ) argue for it being logical target for vaccines. The demonstration that intact BauA was protective in a mouse infection model provides support for pursuing vaccines targeting this antigen ( 18 ).…”

“…While all three siderophore associated loci are known to be upregulated during iron restriction in vitro and in vivo, it is in fact the inactivation of the acinetobactin biosynthesis pathway that attenuates survival of A. baumannii in a murine model (14). Additionally, the acinetobactin locus is highly conserved amongst A. baumannii clinical isolates (14, 16) further suggesting that acinetobactin is critical to supporting A. baumannii survival and virulence. Thus, designing novel therapeutics that target this essential siderophore system can represent an alternative avenue for neutralizing this pathogen.…”

“…baumannii in a murine model ( 14 ). Additionally, the acinetobactin locus is highly conserved amongst A. baumannii clinical isolates ( 14 , 16 ) further suggesting that acinetobactin is critical to supporting A. baumannii survival and virulence. Thus, designing novel therapeutics that target this essential siderophore system can represent an alternative avenue for neutralizing this pathogen.…”

Lipocalin-2 is an essential component of the innate immune response to Acinetobacter baumannii infection

“…baumannii produces numerous structurally distinct siderophores including acinetobactin and pre-acinetobactin, baumannoferrins A and B, and fimsbactins A through F [ 85 , 86 , 110 , 114 , 138 , 139 ]. To date, only genes within the acinetobactin cluster have been shown to be essential to bacterial survival and dissemination during infection [ 18 , 19 , 22 ]. Although it is not known if any of the A .…”

“…Indeed, our laboratory and others have determined that the acquisition of essential nutrient metals such as iron, zinc, and manganese contribute to the virulence of A . baumannii in vivo [ 18 – 26 ], whereas exposure to disinfectants such as ethanol has been linked to increased biofilm formation and growth of the pathogen both in vitro and in vivo [ 27 – 29 ]. The capacity of A .…”