Discovery of Bioactive Metabolites by Acidic Stress to a Geldanamycin Producer, .

In an effort to activate silent biosynthetic gene clusters, DSM42010, a producer of geldanamycin, was cultured at four different pHs (4.5, 5.4, 6.6, and 7.4). An acidic culture condition (pH 5.4) was selected for a chemical investigation since showed a different metabolic profile compared to when it was cultured under other conditions. Seven new (-) and four known (-) compounds were isolated from these cultures. The structures of the isolated compounds were determined by spectroscopic techniques and chemical derivatization. Relative and absolute configurations of the new compounds (-) were established using BCA, PGME method, advanced Marfey's method, modified Mosher's method, and comparison of observed and calculated ECD data. Interestingly, compounds - were truncated versions of geldanamycin, and compound was also deduced to originate from geldanamycin. Compound was composed of 3-methyltyrosine and 6-hydroxy-2,4-hexadienoic acid connected through an amide bond. Compounds and were dihydrogenated forms of geldanamycin with a hydroxy substitution. It is possible that culturing this strain under acidic conditions interfered to some degree with the geldanamycin polyketide synthase, leading to production of truncated versions as well as analogues of geldanamycin. Compounds , , and showed significant antivirulence activity, inhibiting production of α-toxin by methicillin-resistant without growth attenuation and global regulatory inhibition; compounds , , and may become promising α-toxin-specific antivirulence leads with less risk of resistance development.