| Summary: | 博士 === 國立陽明大學 === 微生物及免疫學研究所 === 103 === Teicoplanin A2-2 (Tei)/A40926 is the last-line antibiotic to treat multidrug-resistant Gram-(+) bacterial infections, e.g. methicillin-resistant Staphylococcus aureus (MRSA)/vancomycin-resistant enterococcus (VRE). This class of antibiotics is empowered by the N-acyltransferase (NAT) Orf11*/Dbv8 through N-acylation on glucosamine at the central residue of Tei/A40926 pseudoaglycone. The enzyme possesses enormous untapped application values, while its advanced development is hampered largely due to lack of structural information. In this report, we present eight high-resolution X-ray crystallographic unary, binary and ternary complexes deciphering the molecular basis for the enzyme functionalities. The enzyme undergoes a multistage conformational change upon binding of acyl-CoA, thus allowing the upload of Tei pseudoaglycone to enable the acyl-transfer reaction to take place in the occlusion of the N- and C-halves of the protein. The acyl moiety of acyl-CoA can be bulky or lengthy to be transferred to form new derivatives to a large extent of diversity. Vancomycin/synthetic acyl-N-acetyl cysteamine was unexpected able to serve as a surrogate of an acyl acceptor/donor, respectively. Most strikingly, the enzyme can catalyze formation of 2N,6O-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.
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