Antibacterial Paramagnetic Quinones from Actinoallomurus

Abstract

Four metabolites, designated paramagnetoquinone A, B, C, and D (1-4), were isolated from three strains belonging to the actinomycete genus Actinoallomurus. Compounds 1 and 2 showed potent antibacterial activity with MIC values lower than 0.015 μg/mL against Gram-positive pathogens, including antibiotic-resistant strains. Since compounds 1 and 2 were NMR-silent due to the presence of an oxygen radical, structure elucidation was achieved through a combination of derivatizations, oxidations, and analysis of C-labeled compounds. The paramagnetoquinones share the same carbon scaffold as tetracenomycin but carry two quinones and a five-membered lactone fused to the aromatic system. Compounds 2 and 1 are identical except for an unprecedented replacement of a methoxy in 2 by a methylamino group in 1. Related compounds devoid of methyl group(s) and of antibacterial activity were isolated from a different Actinoallomurus strain. The likely pmq biosynthetic gene cluster was identified from strain ID145113. While the cluster encodes many of the expected enzymes involved in the formation of aromatic polyketides, it also encodes a dedicated ketoacid dehydrogenase complex and an unusual acyl carrier protein transacylase, suggesting that an unusual starter unit might prime the polyketide synthase.

Novel Polyethers from Screening Actinoallomurus spp.

“…During the course of our screening, we frequently encountered strains producing aromatic polyketides. Identified products included the allocyclinones, hyper-halogenated angucyclinones detected from twelve independent strains belonging to three different phylotypes [ 17 ]; the paramagnetoquinones, highly paramagnetic tetracenes produced by three independent strains belonging to three different phylotypes [ 18 ]; three producers of the related dihydrobenzo-(alpha)-naphthacenequinones pradimicin (strains ID145114 and ID145318) and benanomicin (strain ID145226) (see Supplementary Materials Figure S6 ). Pradimicin and benanomicin present a common polyketide core decorated with a disaccharide unit and differ for the presence/absence of an N -methyl on the aminated-sugar.…”

“…The octacyclomycin producer ID145817 is less closely related (≤99.1% identity) to A. bryophytorum and A. yoronensis , although all these strains belong to a related phylogenetic branch. The α-770 producer, instead, is distantly related to A. spadix (98.7% identity) and belongs to an unrelated branch that includes, among others, strain ID145113, the producer of the aromatic polyketide paramagnetoquinone [ 18 ]. Remarkably, all polyether-producing Actinoallomurus strains were isolated from soil samples of tropical origin ( Table 2 ), notwithstanding that 64% of the screened strains were of non-tropical origin (mostly from Europe; see Table 1 ).…”

“…Strains belonging to the genus Actinoallomurus have been shown to produce a variety of metabolites [ 12 , 15 , 16 , 17 , 18 , 19 ] originating from different biosynthetic pathways. In this study, we explored 200 randomly picked Actinoallomurus isolates from the NAICONS strain collection.…”

“…In this study, we explored 200 randomly picked Actinoallomurus isolates from the NAICONS strain collection. Together with the metabolites previously described [ 16 , 17 , 18 , 19 ], we analyzed the antibacterial compounds produced by 37 strains. This set of compounds includes two novel polyethers, as described here.…”

Oxidative Stress-Generating Antimicrobials, a Novel Strategy to Overcome Antibacterial Resistance

“…Quinones are compounds that can be produced as secondary metabolites by Actinoallomorus and Streptomyces sp. [113,114] and show antimicrobial activity against important pathogens such as Enterococcus sp., Streptococcus sp., Staphylococcus sp., or Moraxela catarrhalis [113]. Most importantly, quinones are active against methicillin-resistant S. aureus [114], which is a facultative intracellular pathogen [115].…”