Glenthmycins A-M: Macrocyclic Spirotetronate Polyketide Antibacterials from the Australian Pasture Plant-Derived sp. CMB-PB041.

Chemical investigation of Australian pasture plant-derived sp. CMB-PB041, supported by miniaturized cultivation profiling and molecular network analysis, led to the isolation and characterization of 13 new macrocyclic spirotetronates, glenthmycins A-M (-), with structures assigned by detailed spectroscopic analysis, chemical degradation and derivatization, and mechanistic and biosynthetic considerations. Hydrolysis of glenthmycin B () yielded the aglycone , whose structure and absolute configuration were secured by X-ray analysis, along with the unexpected amino sugar residues glenthose lactams A () and B (), with Mosher analysis of facilitating assignment of absolute configurations of the amino sugar. While the glenthmycins proved to be acid stable, treatment of isomeric glenthmycins (i.e., , , and ) with base catalyzed rapid intramolecular -esterification to regio-isomeric mixtures (i.e., + + ). Exposure of to base achieved the same intramolecular -esterification and was instrumental in detecting and tentatively identifying two additional minor co-metabolites, glenthmycins N () and O (). A structure-activity relationship analysis carried out on - and the semisynthetic analogues and - revealed a promising Gram +ve antibacterial pharmacophore, effective against methicillin-resistant (MRSA) and vancomycin-resistant Enterococci (VRE), but with no detectable cytotoxicity to eukaryotic cells (i.e., fungal and human carcinoma). Of particular note, the semisynthetic analogue glenthmycin K 9-valerate () was unique among glenthmycins in potently inhibiting growth of the full panel of Gram +ve pathogens (IC 0.2-1.6 μM). We conclude with an observation that any future evaluation of the antibacterial potential of glenthmycins and related macrocyclic spirotetronates may do well to include important soil-derived Gram +ve pathogens, such as , , and , the causative agents of anthrax, botulism, and livestock pneumonia.