Abstract
New infectious diseases and increase in drug-resistant microbial pathogens emphasize the need for antibiotics with novel mode-of-action. Tetramates represented by fungi-derived tenuazonic acid and bacterial polycyclic tetramate macrolactams (PTMs) are an important family of natural products with a broad spectrum of antimicrobial activities. Despite their potential application as new antibiotics, it remains unknown how PTMs function. In this study, genomic mining revealed that PTM biosynthetic gene clusters (BGCs) are widespread in both Gram-positive and Gram-negative bacteria, and we investigated a sponge endosymbiont Actinoalloteichus hymeniacidonis harboring a potential PTM-BGC. Xanthobaccin A that previously has only been isolated from a Gram-negative bacterium was obtained after a scale-up fermentation, isolation, and structure elucidation through mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. Xanthobaccin A as well as two previously reported tetramates, equisetin and ikarugamycin, exhibited antibacterial activities against Bacillus subtilis. In addition, these three tetramates were for the first time to be confirmed as metallophores and the stoichiometry of the complexes were shown to be Fe(III)(equisetin)3/Fe(III)(equisetin)2 and Fe(III)(ikarugamycin)2, respectively. Meanwhile, we found that all three tetramates could reduce ferric into ferrous iron, which triggers the Fenton chemistry reaction. Their antibacterial activity was reduced by adding the radical scavenger, vitamin C. Altogether, our work demonstrates that equisetin and PTMs can act as metallophores and their antimicrobial mechanism is possibly mediated through Fenton chemistry.
Highlights
The increase in drug-resistant pathogenic microorganisms is a major societal challenge (Cooper and Shlaes, 2011) and the development of antibiotics with novel mode-of-action is urgently needed
The biosynthesis was proposed to be carried out by a hybrid iterative PKS-NRPS, and a single set of the functional domains KS-AT-DH-KR-ACP that iteratively incorporate six malonyl-CoA to form two polyene chains, which were further condensed with the two free amine groups of L-ornithine via the NRPS activity. This resulted in a tetramatepolyene intermediate, which was cyclized via reduction by the tailoring oxidative enzymes to form the polycyclic tetramate macrolactams (PTMs) skeleton
Given the metallophore and antibiotics activity, we propose that one potential ecological role of PTMs in the natural ecosystem is to chelate Fe3+ in the vicinity of hyphae at low pH, which restrains the reduction of Fe3+ and initiation of Fenton chemistry on-site (Figure 4)
Summary
The increase in drug-resistant pathogenic microorganisms is a major societal challenge (Cooper and Shlaes, 2011) and the development of antibiotics with novel mode-of-action is urgently needed. Natural products with metal-chelating properties have a great potential for the development of new antibiotics. PTMs are Bioactive Metallophores products with metal-chelating properties, and some derivatives exhibit profound activities against multidrug-resistant bacteria (Dandawate et al, 2019). Natural products containing a tetramate-moiety (Figure 1) represent an important class of bioactive compounds with a broad spectrum of antimicrobial activities. Tenuazonic acid can complex with copper, iron, nickel, and magnesium ions (Lebrun et al, 1985) and it has been suggested that the biological activity of tetramates is related to their metal-complexing ability (Steyn and Rabie 1976). Enolic tautomers of tenuazonic acids exist, their crystal structure has revealed a square-planar Cu(II) complex with a Z-enol form in which the amide and acetyl oxygen atoms are bound to the metal (Dippenaar et al, 1977).
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