Microcin
C and related antibiotics are Trojan-horse peptide-adenylates.
The peptide part is responsible for facilitated transport inside the
sensitive cell, where it gets processed to release a toxic warhead—a
nonhydrolyzable aspartyl-adenylate, which inhibits aspartyl-tRNA synthetase.
Adenylation of peptide precursors is carried out by MccB THIF-type
NAD/FAD adenylyltransferases. Here, we describe a novel microcin C-like
compound from Bacillus amyloliquefaciens. The B. amyloliquefaciens MccB demonstrates an unprecedented
ability to attach a terminal cytidine monophosphate to cognate precursor
peptide in cellular and cell free systems. The cytosine moiety undergoes
an additional modification—carboxymethylation—that is
carried out by the C-terminal domain of MccB and the MccS enzyme that
produces carboxy-SAM, which serves as a donor of the carboxymethyl
group. We show that microcin C-like compounds carrying terminal cytosines
are biologically active and target aspartyl-tRNA synthetase, and that
the carboxymethyl group prevents resistance that can occur due to
modification of the warhead. The results expand the repertoire of
known enzymatic modifications of peptides that can be used to obtain
new biological activities while avoiding or limiting bacterial resistance.
A novel strategy for direct aryl hydroxylation via Pd-catalysed Csp(2)-H activation through an unprecedented hydroxyl radical transfer from 1,4-dioxane, used as a solvent, is reported with bio relevant and sterically hindered heterocycles and various acyclic functionalities as versatile directing groups.
Aminoacyl-tRNA synthetases (aaRSs) are enzymes that precisely attach an amino acid to its cognate tRNA. This process, which is essential for protein translation, is considered a viable target for the development of novel antimicrobial agents, provided species selective inhibitors can be identified. Aminoacyl-sulfamoyl adenosines (aaSAs) are potent orthologue specific aaRS inhibitors that demonstrate nanomolar affinities in vitro but have limited uptake. Following up on our previous work on substitution of the base moiety, we evaluated the effect of the N-position of the adenine by synthesizing the corresponding 3-deazaadenosine analogues (aaS3DAs). A typical organism has 20 different aaRS, which can be split into two distinct structural classes. We therefore coupled six different amino acids, equally targeting the two enzyme classes, via the sulfamate bridge to 3-deazaadenosine. Upon evaluation of the inhibitory potency of the obtained analogues, a clear class bias was noticed, with loss of activity for the aaS3DA analogues targeting class II enzymes when compared to the equivalent aaSA. Evaluation of the available crystallographic structures point to the presence of a conserved water molecule which could have importance for base recognition within class II enzymes, a property that can be explored in future drug design efforts.
Simple, convenient, and green synthetic protocols have been developed for the one pot synthesis of 2,3-disubstituted quinazolin-4(3H)-ones and 2-styryl-3-substituted quinazolin-4(3H)-ones under catalyst and solvent free conditions.
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