Several metal-based carbon monoxide-releasing molecules (CORMs) are active CO donors with established antibacterial activity. Among them, CORM conjugates with azole antibiotics of type [Mn(CO) 3 (2,2′-bipyridyl)(azole)] + display important synergies against several microbes. We carried out a structure−activity relationship study based upon the lead structure of [Mn(CO) 3 (Bpy)(Ctz)] + by producing clotrimazole (Ctz) conjugates with varying metal and ligands. We concluded that the nature of the bidentate ligand strongly influences the bactericidal activity, with the substitution of bipyridyl by small bicyclic ligands leading to highly active clotrimazole conjugates. On the contrary, the metal did not influence the activity. We found that conjugate [Re(CO) 3 (Bpy)(Ctz)] + is more than the sum of its parts: while precursor [Re(CO) 3 (Bpy)Br] has no antibacterial activity and clotrimazole shows only moderate minimal inhibitory concentrations, the potency of [Re(CO) 3 (Bpy)(Ctz)] + is one order of magnitude higher than that of clotrimazole, and the spectrum of bacterial target species includes Gram-positive and Gram-negative bacteria. The addition of [Re(CO) 3 (Bpy)(Ctz)] + to Staphylococcus aureus causes a general impact on the membrane topology, has inhibitory effects on peptidoglycan biosynthesis, and affects energy functions. The mechanism of action of this kind of CORM conjugates involves a sequence of events initiated by membrane insertion, followed by membrane disorganization, inhibition of peptidoglycan synthesis, CO release, and break down of the membrane potential. These results suggest that conjugation of CORMs to known antibiotics may produce useful structures with synergistic effects that increase the conjugate's activity relative to that of the antibiotic alone.
Acyldepsipeptide (ADEP) is an exploratory antibiotic with a novel mechanism of action. ClpP, the proteolytic core of the caseinolytic protease, is deregulated towards unrestrained proteolysis. Here, we report on the mechanism of ADEP resistance in Firmicutes. This bacterial phylum contains important pathogens that are relevant for potential ADEP therapy. For Staphylococcus aureus , Bacillus subtilis , enterococci and streptococci, spontaneous ADEP‐resistant mutants were selected in vitro at a rate of 10 −6 . All isolates carried mutations in clpP . All mutated S. aureus ClpP proteins characterised in this study were functionally impaired; this increased our understanding of the mode of operation of ClpP. For molecular insights, crystal structures of S. aureus ClpP bound to ADEP4 were determined. Well‐resolved N‐terminal domains in the apo structure allow the pore‐gating mechanism to be followed. The compilation of mutations presented here indicates residues relevant for ClpP function and suggests that ADEP resistance will occur at a lower rate during the infection process.
The increasing number of available genomes,i n combination with advanced genome mining techniques,u nveiled ap lethora of biosynthetic gene clusters (BGCs) coding for ribosomally synthesized and post-translationally modified peptides (RiPPs). The products of these BGCs often represent an enormous resource for new and bioactive compounds,b ut frequently,they cannot be readily isolated and remain cryptic. Here,w ed escribe at unable metabologenomic approach that recruits asynergism of bioinformatics in tandem with isotopeand NMR-guided platform to identify the product of an orphan RiPP gene cluster in the genomes of Nocardia terpenica IFM 0406 and 0706 T .T he application of this tactic resulted in the discovery of nocathioamides family as afounder of anew class of chimeric lanthipeptides I.
We report a genomics‐guided exploration of the metabolic potential of the brasilicardin producer strain Nocardia terpenica IFM 0406. Bioinformatics analysis of the whole genome sequence revealed the presence of a biosynthetic gene cluster presumably responsible for the generation of formerly unknown nocobactin derivatives. Mass spectrometry‐assisted isolation led to the identification of three new siderophores, terpenibactins A ( 1 ), B ( 2 ) and C ( 3 ), which belong to the class of nocobactins. Their structures were elucidated by employing spectroscopic techniques. Compounds 1 – 3 demonstrated inhibitory activity towards the muscarinic M3 receptor, while exhibiting only a low cytotoxicity.
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