Antisense-Guided Isolation and Structure Elucidation of Pannomycin, a Substituted cis-Decalin from Geomyces pannorum

Abstract

Antisense-based screening strategies can be used to sensitize a microorganism and selectively detect inhibitors against a particular cellular target of interest. A strain of Staphylococcus aureus that generates an antisense RNA against SecA,a central member of the protein secretion machinery, has been used to screen for novel antibacterials. Possible inhibitors of the SecA ATP-ase were selected with a high-throughput, two-plate agar-based whole cell differential sensitivity screen. After screening a library of over 115 000 natural products extracts with the SecA antisense strain, an extract of Geomyces pannorum was identified as providing increased activity against the sensitized strain as compared with the wild-type control. Bioassay-guided isolation of the active component from this fungal extract provided a new cis-decalin secondary metabolite, which we have named pannomycin.

Living strategy of cold-adapted fungi with the reference to several representative species

“…Some bioactive metabolites also have pharmaceutical potentials, such as pannomycin, structurally similar to a compound known to inhibit the ATPase, SecA, in the bacterial translocase pathway (Parish et al . 2009). Additional metabolites have been isolated from P. pannorum including antimicrobial asterric acid derivatives called “geomycins”, which is active against Aspergillus fumigatus , as well as Gram-positive and Gram-negative bacteria (Li et al 2008).…”

Bacterial Antisense RNAs: How Many Are There, and What Are They Doing?

“…Since antisense RNAs allow for the conditional repression of target genes, they also have been employed to study bacterial growth and metabolism (6, 27, 40, 76, 110) and to characterize known or putative virulence factors (38, 65). Antisense RNAs have been used to sensitize other bacteria to antibiotics (37, 39, 44), identify novel antibiotics (73, 123), identify antibiotic targets (29, 32, 39), or clarify the mechanisms of action of potential new drugs (39). In addition, antisense technology has allowed the induction of “bacterial suicide” without the need for antimicrobial compounds.…”

Chapter 11. Novel Approaches to Exploit Natural Products from Microbial Resources

“…This cis-decalin natural product is structurally similar to known inhibitors of SecA cissetin and CJ-21,058. 58,59 When the compound was tested on a panel of microorganisms, only weak antimicrobial activity was observed with MICs of 1.4 mM against S. aureus Smith and Enterococcus faecalis, and activity was observed at this concentration against Streptococcus pneumoniae, H. influenzae and Escherichia coli. 58 …”