Bacteria of the genus Pandoraea have not been studied much to date. Their name is reminiscent of Pandora's box from Greek mythology, which is a symbol of uncontrollable dangers. "We have been working with an antibiotic-resistant bacterium," says Elena Herzog. She is the first author of the publication and works as a doctoral researcher in the team of Christian Hertweck, the head of the study at the Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI). However, like so many things in nature, these pathogenic bacteria do not only have negative properties. "Pandoraea bacteria not only harbor risks. They also produce natural products with an antibacterial effect."
Despite the high health risk posed by Pandoraea, their molecular properties were hardly known until now. "We only knew that these bacteria occur in nature and that they can be pathogenic because they have been found in the lung microbiome of patients with cystic fibrosis or sepsis," explains Herzog.
The race for iron
As for most living organisms, iron is also essential for bacteria. "Iron plays a central role in enzymes and the respiratory chain of living organisms, for example," explains Herzog. Particularly in iron-poor environments such as the human body, the conditions for sufficient absorption of the element are anything but ideal. Many microorganisms therefore produce so-called siderophores: small molecules that bind iron from the environment and transport it into the cell.
"However, there were no known virulence or niche factors in the Pandoraea bacteria that could help them survive," says Herzog. The research team therefore wanted to find out how Pandoraea strains can survive in such a competitive environment.
Using bioinformatic analyses, the team identified a previously unknown gene cluster called pan. It codes for a non-ribosomal peptide synthetase – a typical enzyme for the production of siderophores. "We started with a gene cluster analysis and specifically searched for genes that could be responsible for the production of siderophores," reports Herzog.
Through targeted inactivation of genes as well as culture-based methods and state-of-the-art analytical techniques – including mass spectrometry, NMR spectroscopy, chemical degradation and derivatization – the researchers from Jena succeeded in isolating two new natural products and elucidating their chemical structure: Pandorabactin A and B. Both are able to complex iron and could play an important role in how Pandoraea strains survive in difficult environments. "The molecules help the bacteria to take up iron when it is scarce in their environment," says Herzog.
Less iron, fewer competitors
Bioassays have also shown that pandorabactins inhibit the growth of other bacteria such as Pseudomonas, Mycobacterium and Stenotrophomonas by removing iron from these competitors.
Analyses of sputum samples from the lungs of cystic fibrosis patients further revealed that the detection of the pan gene cluster correlates with changes in the lung microbiome. Pandorabactins could therefore have a direct influence on microbial communities in diseased lungs.
"However, it is still too early to derive medical applications from these findings," emphasizes Herzog. Nevertheless, the discovery provides important information on the survival strategies of bacteria of the genus Pandoraea and on the complex competition for vital resources in the human body.
The study was carried out in close cooperation between the Leibniz-HKI and the universities of Jena, Heidelberg and Hong Kong. It was conducted as part of the "Balance of the Microverse" Cluster of Excellence and the ChemBioSys Collaborative Research Center and was funded by the German Research Foundation. The imaging mass spectrometer used for the analyses was funded by the Free State of Thuringia and co-financed by the European Union.
