Structure and Biosynthetic Assembly of Gulmirecins, Macrolide Antibiotics from the Predatory Bacterium Pyxidicoccus fallax

Abstract

The gulmirecins constitute a new class of glycosylated macrolides that were isolated from the predatory bacterium Pyxidicoccus fallax HKI 727. Their structures were solved by a combination of NMR spectroscopic experiments and chemical derivatization. Analysis of the annotated gulmirecin gene cluster complemented the configurational assignment and provided insights into the stereochemical course of the biosynthetic assembly. The gulmirecins exhibit strong activity against staphylococci, including methicillin-resistant Staphylococcus aureus, but no cytotoxic effects on human cells.

Total Synthesis of Disciformycin A and B: Unusually Exigent Targets of Biological Significance

“…[2,3] It is against this backdropt hat the recent reports on the myxobacterialm etabolites of the disciformycina nd gulmirecin families must be seen (Figure 1). [4][5][6][7] These compounds exhibit considerable activity against Gram-positiveb acteria, including several methicillin-or vancomycin-resistant Staphyllococcus aureus strains;m ost notably,t hey seem to address an as yet unknown biological targeta nd hence likelyp rovide new opportunities in the quest for antibiotics devoid of cross-resistance with approved drugs.The constitution and stereostructure of these remarkable polyketides were determined by two independentg roups, each of which masterfullyc omplemented the spectroscopica rgumentsb ya na nalysis of the encoding gene cluster. [4,5] One of these studies suggestedt hat disciformycin B( 2,F igure 1) represents the primary product of biosynthesis;i nterestingly, 2 also proved considerably more active than its sibling 1 in an assay comprising eight different bacterial strains.…”

“…[4,5] One of these studies suggestedt hat disciformycin B( 2,F igure 1) represents the primary product of biosynthesis;i nterestingly, 2 also proved considerably more active than its sibling 1 in an assay comprising eight different bacterial strains. [4] Yet, preliminary evidence suggests that 2 is fragile and subject to irreversible double bond migration, which is likelyd riven by the highers tabilityo ft he trisubstituted enoate in 1 compared to the disubstituted enonemotif in the parent compound 2.Intrigued by the biologicalp romisea nd the synthetic challenge forecastb yt hese reports, [4,5] we embarked into ap rogram aiming at ac hemical investigation of this familyo fn ew lead compounds. To tal synthesis is the first step to be taken in order to assess the ingrained metastabilityo f2 in more detail and scout possible remedies.A tthe same time, it is desirable to identify promising sites for late-stage modification to be addressed in then ext phase of the project.…”

“…[2,3] It is against this backdropt hat the recent reports on the myxobacterialm etabolites of the disciformycina nd gulmirecin families must be seen (Figure 1). [4][5][6][7] These compounds exhibit considerable activity against Gram-positiveb acteria, including several methicillin-or vancomycin-resistant Staphyllococcus aureus strains;m ost notably,t hey seem to address an as yet unknown biological targeta nd hence likelyp rovide new opportunities in the quest for antibiotics devoid of cross-resistance with approved drugs.…”

“…Intrigued by the biologicalp romisea nd the synthetic challenge forecastb yt hese reports, [4,5] we embarked into ap rogram aiming at ac hemical investigation of this familyo fn ew lead compounds. To tal synthesis is the first step to be taken in order to assess the ingrained metastabilityo f2 in more detail and scout possible remedies.A tthe same time, it is desirable to identify promising sites for late-stage modification to be addressed in then ext phase of the project.…”

“…[4,5] One of these studies suggestedt hat disciformycin B( 2,F igure 1) represents the primary product of biosynthesis;i nterestingly, 2 also proved considerably more active than its sibling 1 in an assay comprising eight different bacterial strains. [4] Yet, preliminary evidence suggests that 2 is fragile and subject to irreversible double bond migration, which is likelyd riven by the highers tabilityo ft he trisubstituted enoate in 1 compared to the disubstituted enonemotif in the parent compound 2.…”