title: Multiple complexes of long aliphatic N-acyltransferases lead to synthesis of 2,6-diacylated/2-acyl-substituted glycopeptide antibiotics, effectively killing vancomycin-resistant enterococcus.
abstract: Teicoplanin A2-2 (Tei)/A40926 is the last-line antibiotic to treat multidrug-resistant Gram-positive bacterial infections, e.g., methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE). This class of antibiotics is powered by the N-acyltransferase (NAT) Orf11*/Dbv8 through N-acylation on glucosamine at the central residue of Tei/A40926 pseudoaglycone. The NAT enzyme possesses enormous value in untapped applications; its advanced development is hampered largely due to a lack of structural information. In this report, we present eight high-resolution X-ray crystallographic unary, binary, and ternary complexes in order to decipher the molecular basis for NAT's functionality. The enzyme undergoes a multistage conformational change upon binding of acyl-CoA, thus allowing the uploading of Tei pseudoaglycone to enable the acyl-transfer reaction to take place in the occlusion between the N- and C-halves of the protein. The acyl moiety of acyl-CoA can be bulky or lengthy, allowing a large extent of diversity in new derivatives that can be formed upon its transfer. Vancomycin/synthetic acyl-N-acetyl cysteamine was not expected to be able to serve as a surrogate for an acyl acceptor/donor, respectively. Most strikingly, NAT can catalyze formation of 2-N,6-O-diacylated or C6→C2 acyl-substituted Tei analogues through an unusual 1,4-migration mechanism under stoichiometric/solvational reaction control, wherein selected representatives showed excellent biological activities, effectively counteracting major types (VanABC) of VRE.
authors.affiliation: Genomics Research Center, Academia Sinica , Taipei 115, Taiwan.
authors.forename: Syue-Yi
authors.initials: SY
authors.lastname: Lyu
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Liu
authors.forename: Chin-Yuan
authors.initials: CY
authors.lastname: Chang
authors.forename: Chuen-Jiuan
authors.initials: CJ
authors.lastname: Huang
authors.forename: Ya-Huang
authors.initials: YH
authors.lastname: Chiu
authors.forename: Chun-Man
authors.initials: CM
authors.lastname: Huang
authors.forename: Ning-Shian
authors.initials: NS
authors.lastname: Hsu
authors.forename: Kuan-Hung
authors.initials: KH
authors.lastname: Lin
authors.forename: Chang-Jer
authors.initials: CJ
authors.lastname: Wu
authors.forename: Ming-Daw
authors.initials: MD
authors.lastname: Tsai
authors.forename: Tsung-Lin
authors.initials: TL
authors.lastname: Li
mesh_terms: D000215:Acylation; D000217:Acyltransferases / Q000737:chemistry / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D055162:Biocatalysis; D060326:Chemistry Techniques, Synthetic; D006020:Glycopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D065507:Vancomycin-Resistant Enterococci / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D000217:Acyltransferases