Darobactin is an experimental antibiotic compound that may be effective against Gram-negative bacteria. If it can be developed into a human-compatible form it would be the first to come from an animal microbiome.[1]
The compound was discovered in Photorhabdus bacteria in 2019, living in the digestive systems of entomopathogenic nematodes.[2] Researchers identified the nematode as a possible host because they feed on insects by targeting their larvae and releasing bacteria that then confront pathogens similar to those found in humans.[1]
Gram-negative bacteria have a characteristic architecture for the cell envelope, with an inner membrane, an outer membrane, and a periplasmic space in between. In this arrangement, the peptidoglycan layer is relatively thin and does not retain the crystal violet stain used in the Gram staining method of bacterial classification. Antibiotic resistance has become widespread in bacterial pathogens, and in Gram-negative bacteria such as the Enterobacteriaceae, much of this comes from acquired genes. The resistance genes encode proteins that export or inactivate β-lactam antibiotics, aminoglycosides, tetracycline, chloramphenicol, fosfomycin, etc. Plasmids carrying these genes readily move between strains or between species. Consequently, resistance to the currently available panel of approved antibiotics is an increasingly worrisome problem.[1] The most recent class of antibiotics effective against these bacteria emerged in the 1960s.[2]
Mode of actionedit
Darobactin inhibits BamA and disrupts the proper formation of the Gram-negative cell envelope.[2] BamA is a central component of the BamABCDE complex, which inserts proteins from the periplasm into the outer membrane. BamA also aids in the folding of outer membrane-bound proteins. Thus, darobactin prevents the proper formation of the outer membrane of bacteria, leading to cell death.[1] Because only Gram-negative bacteria have BamA and outer membrane beta-barrel proteins, only they are susceptible to darobactin.
Biosynthesisedit
Darobactin is a RiPP, that is, a ribosomally synthesized and post-translationally modified peptide. Its production and export is encoded by a typically silent five gene operon that showed minimal production under laboratory culture conditions. Mature darobactin consists of a seven amino acids core peptide derived from a longer precursor, with unusual Trp-1 to Trp-3 and Trp-3 to Lys-5 (or Arg-5, in variant forms) crosslinks.[2] The key enzyme for maturation from the precursor to the mature form is the radical SAM/SPASM enzyme DarE.
Referencesedit
^ abcdeNield, David (24 November 2019). "A Tiny Worm Has Been Found Carrying New Antibiotic That Could Help Us Fight Superbugs". ScienceAlert. from the original on 2019-11-25. Retrieved 2019-11-26.
darobactin, experimental, antibiotic, compound, that, effective, against, gram, negative, bacteria, developed, into, human, compatible, form, would, first, come, from, animal, microbiome, identifiers, model, jsmol, interactive, image, pubchem, 154586077, inchi. Darobactin is an experimental antibiotic compound that may be effective against Gram negative bacteria If it can be developed into a human compatible form it would be the first to come from an animal microbiome 1 Darobactin Identifiers 3D model JSmol Interactive image PubChem CID 154586077 InChI InChI 1S C47H55N11O12 c48 13 5 9 25 23 11 12 30 27 15 23 28 19 51 30 40 39 58 42 63 31 17 36 50 61 53 41 62 29 49 16 24 18 52 37 26 24 8 4 10 35 37 70 40 46 67 56 34 21 60 44 65 57 38 25 45 66 55 33 20 59 43 64 54 32 47 68 69 14 22 6 2 1 3 7 22 h1 4 6 8 10 12 15 18 19 25 29 31 34 38 40 51 52 59 60H 5 9 13 14 16 17 20 21 48 49H2 H2 50 61 H 53 62 H 54 64 H 55 66 H 56 67 H 57 65 H 58 63 H 68 69 t25 29 31 32 33 34 38 39 40 m0 s1Key IAOIRKWNLBCFFO KUDSBEMESA N SMILES NCCC C H 1 C H NC O C H CO NC O C H 2NC O C H CC N O NC O C H N CC3 CNC4 C3C CC C4O C H 2C2 CNC3 CC C1C C23 C O N C H CO C O N C H CC1 CC CC C1 C O O Properties Chemical formula C 47H 55N 11O 12 Molar mass 966 022 g mol 1 Except where otherwise noted data are given for materials in their standard state at 25 C 77 F 100 kPa Infobox references Contents 1 History 2 Gram negative bacteria 3 Mode of action 4 Biosynthesis 5 ReferencesHistory editThe compound was discovered in Photorhabdus bacteria in 2019 living in the digestive systems of entomopathogenic nematodes 2 Researchers identified the nematode as a possible host because they feed on insects by targeting their larvae and releasing bacteria that then confront pathogens similar to those found in humans 1 In experiments it cured mice of infections with Escherichia coli and Klebsiella pneumoniae both members of the Enterobacteriaceae without toxic side effects 1 Gram negative bacteria editGram negative bacteria have a characteristic architecture for the cell envelope with an inner membrane an outer membrane and a periplasmic space in between In this arrangement the peptidoglycan layer is relatively thin and does not retain the crystal violet stain used in the Gram staining method of bacterial classification Antibiotic resistance has become widespread in bacterial pathogens and in Gram negative bacteria such as the Enterobacteriaceae much of this comes from acquired genes The resistance genes encode proteins that export or inactivate b lactam antibiotics aminoglycosides tetracycline chloramphenicol fosfomycin etc Plasmids carrying these genes readily move between strains or between species Consequently resistance to the currently available panel of approved antibiotics is an increasingly worrisome problem 1 The most recent class of antibiotics effective against these bacteria emerged in the 1960s 2 Mode of action editDarobactin inhibits BamA and disrupts the proper formation of the Gram negative cell envelope 2 BamA is a central component of the BamABCDE complex which inserts proteins from the periplasm into the outer membrane BamA also aids in the folding of outer membrane bound proteins Thus darobactin prevents the proper formation of the outer membrane of bacteria leading to cell death 1 Because only Gram negative bacteria have BamA and outer membrane beta barrel proteins only they are susceptible to darobactin Biosynthesis editDarobactin is a RiPP that is a ribosomally synthesized and post translationally modified peptide Its production and export is encoded by a typically silent five gene operon that showed minimal production under laboratory culture conditions Mature darobactin consists of a seven amino acids core peptide derived from a longer precursor with unusual Trp 1 to Trp 3 and Trp 3 to Lys 5 or Arg 5 in variant forms crosslinks 2 The key enzyme for maturation from the precursor to the mature form is the radical SAM SPASM enzyme DarE References edit a b c d e Nield David 24 November 2019 A Tiny Worm Has Been Found Carrying New Antibiotic That Could Help Us Fight Superbugs ScienceAlert Archived from the original on 2019 11 25 Retrieved 2019 11 26 a b c d Imai Yu Meyer Kirsten J Iinishi Akira Favre Godal Quentin Green Robert Manuse Sylvie Caboni Mariaelena Mori Miho Niles Samantha Ghiglieri Meghan Honrao Chandrashekhar 2019 11 20 A new antibiotic selectively kills Gram negative pathogens Nature 576 7787 459 464 Bibcode 2019Natur 576 459I doi 10 1038 s41586 019 1791 1 ISSN 1476 4687 PMC 7188312 PMID 31747680 Retrieved from https en wikipedia org w index php title Darobactin amp oldid 1198242432, wikipedia, wiki, book, books, library,
