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

Abstract

Chemical investigation of Australian pasture plant-derived Streptomyces 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 (1−13), with structures assigned by detailed spectroscopic analysis, chemical degradation and derivatization, and mechanistic and biosynthetic considerations. Hydrolysis of glenthmycin B (2) yielded the aglycone 14, whose structure and absolute configuration were secured by X-ray analysis, along with the unexpected amino sugar residues glenthose lactams A (15) and B ( 16), with Mosher analysis of 15 facilitating assignment of absolute configurations of the amino sugar. While the glenthmycins proved to be acid stable, treatment of isomeric glenthmycins (i.e., 3, 6, and 8) with base catalyzed rapid intramolecular transesterification to regio-isomeric mixtures (i.e., 3 + 6 + 8). Exposure of 5 to base achieved the same intramolecular trans-esterification and was instrumental in detecting and tentatively identifying two additional minor co-metabolites, glenthmycins N (19) and O (20). A structure−activity relationship analysis carried out on 1−13 and the semisynthetic analogues 14 and 21−26 revealed a promising Gram +ve antibacterial pharmacophore, effective against methicillin-resistant Staphylococcus aureus (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 (26) was unique among glenthmycins in potently inhibiting growth of the full panel of Gram +ve pathogens (IC 50 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 Bacillus anthrax, Clostridium botulinum, and Rhodococcus equi, the causative agents of anthrax, botulism, and livestock pneumonia.

Tetracyclic Steroids Bearing a Bicyclo[4.4.1] Ring System as Potent Antiosteoporosis Agents from the Deep-Sea-Derived Fungus Rhizopus sp. W23

“…It is speculated that the trans-acetylation was initiated by a nucleophilic attack from 24-OH to the adjacent acetyl carbonyl, which was recently reported in the polyketides amaurones 22 and glenthmycins. 23 Likewise, the same 23,24threo-configuration for threo-24-O-acetylneocyclocitrinol (7) was determined by the large value of 3 In addition, another eight known compounds were determined to be neocyclocitrinols B−D (12−14), 5 threo-23-O-methylneocyclocitrinol (15), 5 22-O-acetylisocyclocitrinol A (16), 5 isocyclocitrinols A and B (17, 18), 3 and antineocyclocitrinol A (19) 6 based on comparison of their NMR, MS, and specific rotation data with those published in the literature. Moreover, an X-ray structure was determined for 19.…”

“…Of note, compound 6 was detected to undergo a partial conversion to an isomeric artifact, 7 (C 27 H 38 O 5 ), in MeOH at room temperature (rt), in which the acetyl unit (δ H 2.03; δ C 21.2; 172.5) migrated from C-23 in 6 to C-24 in 7 , supported by the diagnostic HMBC correlation from H-24 (δ H 4.81) to 24-OAc, as well as the deshielding of H-24 (Δδ H +1.04) and shielding of H-23 (Δδ H −0.96) in 7 compared to 6 . It is speculated that the trans -acetylation was initiated by a nucleophilic attack from 24-OH to the adjacent acetyl carbonyl, which was recently reported in the polyketides amaurones and glenthmycins . Likewise, the same 23,24- threo -configuration for threo -24- O -acetylneocyclocitrinol ( 7 ) was determined by the large value of 3 J 23,24 (6.8 Hz).…”

“…It is speculated that the trans-acetylation was initiated by a nucleophilic attack from 24-OH to the adjacent acetyl carbonyl, which was recently reported in the polyketides amaurones 22 and glenthmycins. 23 Likewise, the same 23,24threo-configuration for threo-24-O-acetylneocyclocitrinol (7) was determined by the large value of 3 J 23,24 (6.8 Hz).…”

New Phocoenamicin and Maklamicin Analogues from Cultures of Three Marine-Derived Micromonospora Strains

“…The ester instead of a ketone group located at C-3, which was present in phocoenamicin C ( 5 ) and D ( 1 ) seemed to weaken the activity against MRSA, as previously reported [ 12 ]. Other structurally related families of spirotetronates that have demonstrated strong activities against MRSA are decatromicins [ 29 ], the compounds JK [ 30 ], as well as the recently discovered glenthmycins [ 31 ].…”

Dysambiol, an Anti-inflammatory Secomeroterpenoid from a Dysidea sp. Marine Sponge

“…The assignments were further supported by the NOESY correlations of H-3a/H 3 -18, H 3 -18/H 3 -19, H-17/H 3 -19, and H-14b/H-17. Given the possible rotation around the C-4–C-17 bond, Mosher’s method was used to assign the absolute configuration of 17-OH Figure C).…”