Search

Covering: 1994 to 2019Owing to the rapid increase in nosocomial infections by antibiotic-resistant Acinetobacter baumannii and the paucity of effective treatment options for such infections, interest in the virulence factors involved in its successful dissemination and propagation in the human host have escalated in recent years. Acinetobacin, a siderophore of A. baumannii, is responsible for iron acquisition under nutritional depravation and has been shown to be one of the key virulence factors for this bacterium. In this Highlight, recent findings regarding various chemical and biological aspects of acinetobactin metabolism closely related to the fitness of A. baumannii at the infection sites have been described. In addition, several notable efforts for identifying novel anti-infectious agents based thereon have been discussed.

Acinetobactin is a major siderophore utilized by the human pathogen Acinetobacter baumannii. The rapid acquisition of drug resistance by A. baumannii has garnered concern globally. Herein, acinetobactin and systematically generated analogues were prepared and characterized; the binding and cellular delivery of Fe(III) by the analogues were evaluated. This investigation not only led to the clarification of the physiologically relevant acinetobactin structure but also revealed several key structural elements for its functionality as a siderophore.

Siderophores are high-affinity iron chelators produced and used by bacteria to prosper under iron-limiting conditions they normally encounter in the environment and hosts. In this chapter, we describe the isolation and purification of the siderophores acinetobactin and baumannoferrin produced by the bacterial pathogen Acinetobacter baumannii using XAD-7 batch adsorption and high-pressure liquid chromatography (HPLC). We also describe chemical tests and biological assays used to detect the presence of catechol and hydroxamate siderophores in culture supernatants, XAD-7 extracts, and HPLC fractions.

Total synthesis of anguibactin was accomplished for the first time, and the following biochemical characterizations allowed for the determination of its Fe(III) binding mode as well as the demonstration of its iron delivery capability for Acinetobacter baumannii. These properties, in addition to the thermal stability over acinetobactin, render anguibactin as a competent surrogate siderophore that can be useful for the future development of a siderophore-based antibiotic delivery system against A. baumannii.

Pathogenic Acinetobacter baumannii excrete the siderophore pre-acinetobactin as an iron-scavenging virulence factor. Pre-acinetobactin is a 2,3-dihydroxy-phenyl oxazoline that undergoes pH-dependent isomerization to the isooxazolidinone form acinetobactin in order to expand the pH range for iron acquisition by A. baumannii. In this study we establish important structure-function relationships for the kinetics of isomerization, iron(iii) binding, and siderophore utilization by A. baumannii. We showed that electronic properties of the phenyl oxazoline influence isomerization kinetics and iron(iii) binding. We found that iron(iii) chelation was directly correlated with A. baumannii utilization. Our studies provide important structural and mechanistic insight for understanding how pathogenic A. baumannii uses pre-acinetobactin as a 2-for-1 iron-scavenging siderophore virulence factor.

Pathogenic strains of Acinetobacter baumannii excrete multiple siderophores that enhance iron scavenging from host sources. The oxazoline siderophore pre-acinetobactin undergoes an unusual non-enzymatic isomerization, producing the isoxazolidinone acinetobactin. In this study, we explored the kinetics, mechanism, and biological consequence of this siderophore swapping. Pre-acinetobactin is excreted to the extracellular space where the isomerization to acinetobactin occurs with a pH-rate profile consistent with 5-exo-tet cyclization at C5' with clean stereochemical inversion. Pre-acinetobactin persists at pH6, and acinetobactin is rapidly formed at pH7, matching each siderophore's pH preference for iron(III) chelation and A. baumannii growth promotion. Acinetobactin isomerization provides two siderophores for the price of one, enabling A. baumannii to sequester iron over a broad pH range likely to be encountered during the course of an infection.

New putative iron-uptake genes were identified in published genomes of the opportunistic human pathogen Acinetobacter baumannii, and their occurrence was determined in a genotypically distinct collection of 50 clinical isolates by PCR and Southern blot assays. The results demonstrated that all A. baumannii isolates tested share the coding potential for two endogenous siderophores, a heme-acquisition and a ferrous iron-uptake system. A second heme-uptake cluster was detected in almost two thirds of isolates, without any apparent correlation with the clonal lineage of the strains. The wide distribution of multiple iron-acquisition systems among diverse A. baumannii clinical isolates argues for a contribution of iron uptake to the pathogenicity of this species. (C) 2010 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Pathogenic bacteria survive in iron-limited host environments by using several iron acquisition mechanisms. Acinetobacter baumannii, causing serious infections in compromised patients, produces an iron-chelating molecule, called acinetobactin, which is composed of equimolar quantities of 2,3-dihydroxybenzoic acid (DHBA), L-threonine, and N-hydroxyhistamine, to compete with host cells for iron. Genes that are involved in the production and transport of acinetobactin are clustered within the genome of A. baumannii. A recent study showed that entA, located outside of the acinetobactin gene cluster, plays important roles in the biosynthesis of the acinetobactin precursor DHBA and in bacterial pathogenesis. Therefore, understanding the genes that are associated with the biosynthesis and transport of acinetobactin in the bacterial genome is required. This review is intended to provide a general overview of the genes in the genome of A. baumannii that are required for acinetobactin biosynthesis and transport.