title: A Trojan-Horse Peptide-Carboxymethyl-Cytidine Antibiotic from Bacillus amyloliquefaciens.
abstract: 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.
authors.affiliation: Institute of Gene Biology, Russian Academy of Science , 34/5 Vavilov str., 119334 Moscow, Russia.|A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University , Leninskie Gory 1, Bldg. 40, Moscow 119991, Russia.
authors.forename: Marina
authors.initials: M
authors.lastname: Serebryakova
authors.affiliation: Institute of Gene Biology, Russian Academy of Science , 34/5 Vavilov str., 119334 Moscow, Russia.
authors.forename: Darya
authors.initials: D
authors.lastname: Tsibulskaya
authors.affiliation: Institute of Gene Biology, Russian Academy of Science , 34/5 Vavilov str., 119334 Moscow, Russia.|Skolkovo Institute of Science and Technology , 3 Nobel str., 143026 Moscow, Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Mokina
authors.affiliation: Institute of Gene Biology, Russian Academy of Science , 34/5 Vavilov str., 119334 Moscow, Russia.|Skolkovo Institute of Science and Technology , 3 Nobel str., 143026 Moscow, Russia.
authors.forename: Alexey
authors.initials: A
authors.lastname: Kulikovsky
authors.affiliation: KU Leuven , O&N Rega, Medicinal Chemistry, Herestraat 49 10, B-3000 Leuven, Belgium.
authors.forename: Manesh
authors.initials: M
authors.lastname: Nautiyal
authors.affiliation: KU Leuven , O&N Rega, Medicinal Chemistry, Herestraat 49 10, B-3000 Leuven, Belgium.
authors.forename: Arthur
authors.initials: A
authors.lastname: Van Aerschot
authors.affiliation: Institute of Gene Biology, Russian Academy of Science , 34/5 Vavilov str., 119334 Moscow, Russia.|Skolkovo Institute of Science and Technology , 3 Nobel str., 143026 Moscow, Russia.|Waksman Institute for Microbiology , 190 Frelinghuysen Road, Piscataway, New Jersey 08854-8020, United States.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Severinov
authors.affiliation: Institute of Gene Biology, Russian Academy of Science , 34/5 Vavilov str., 119334 Moscow, Russia.|Skolkovo Institute of Science and Technology , 3 Nobel str., 143026 Moscow, Russia.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Dubiley
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001226:Aspartate-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000069977:Bacillus amyloliquefaciens / Q000737:chemistry*; D001430:Bacteriocins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D019295:Computational Biology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015394:Molecular Structure
chemical_list: D000900:Anti-Bacterial Agents; D001430:Bacteriocins; D004791:Enzyme Inhibitors; C020411:microcin; D001226:Aspartate-tRNA Ligase