Nitro versus Hydroxamate in Siderophores of Pathogenic Bacteria: Effect of Missing Hydroxylamine Protection in Malleobactin Biosynthesis

摘要

Siderophores play a major role as virulence factors of pathogenic bacteria. Known as the strongest Fe~(3+)-binding agents, these structurally diverse compounds are used to scavenge scarcely soluble iron from the human or animal hosts. Strikingly, infamous human pathogenic bacteria like Yersinia pestis, the causative agent of devastating black death epidemics, completely lose their virulence in the absence of a siderophore. Thus, knowledge of a pathogen's siderophore structures and of the corresponding biosynthetic machineries is considered a prerequisite for new therapeutic approaches such as targeting pathogenicity factors and Trojan horse strategies using siderophore-drug conjugates. Over the past two decades, much research has been devoted to elucidating the siderophores of Burkholderia mallei and Burkholderia pseudomallei, the causative agents of the infectious diseases glanders and melioidosis. Infections with these (β-proteobacteria are often lethal, even with the best treatment available. Both species have thus been categorized as potential biological warfare agents, and indeed B. mallei has been abused in World War I to kill enemy horses and mules. Although it has long been known that B. pseudomallei and B. mallei produce two types of siderophores, pyochelin (1 and 2"-epi-l, Figure 1) and malleobactin (2), surprisingly, the structure of the latter has remained obscure. It was only a matter of speculation that malleobactin could be related to the ornibactins (3-5, Scheme 1), hydroxamate siderophores produced by the Burkholderia cepacia complex (Bcc). Here we disclose the unusual structure and absolute configuration of malleobactin, the siderophore of the human pathogenic B. mallei family and reveal the biogenetic origin of an unprecedented aliphatic nitro amino acid.