TY - JOUR
T1 - A biocatalytic approach to capuramycin analogues by exploiting a substrate permissive N-transacylase CapW
AU - Liu, Xiaodong
AU - Jin, Yuanyuan
AU - Cai, Wenlong
AU - Green, Keith D.
AU - Goswami, Anwesha
AU - Garneau-Tsodikova, Sylvie
AU - Nonaka, Koichi
AU - Baba, Satoshi
AU - Funabashi, Masanori
AU - Yang, Zhaoyong
AU - Van Lanen, Steven G.
N1 - Publisher Copyright:
© The Royal Society of Chemistry 2016.
PY - 2016/4/28
Y1 - 2016/4/28
N2 - Using the ATP-independent transacylase CapW required for the biosynthesis of capuramycin-type antibiotics, we developed a biocatalytic approach for the synthesis of 43 analogues via a one-step aminolysis reaction from a methyl ester precursor as an acyl donor and various nonnative amines as acyl acceptors. Further examination of the donor substrate scope for CapW revealed that this enzyme can also catalyze a direct transamidation reaction using the major capuramycin congener as a semisynthetic precursor. Biological activity tests revealed that a few of the new capuramycin analogues have significantly improved antibiotic activity against Mycobacterium smegmatis MC2 155 and Mycobacterium tuberculosis H37Rv. Furthermore, most of the analogues are able to be covalently modified by the phosphotransferase CapP/Cpr17 involved in self resistance, providing critical insight for future studies regarding clinical development of the capuramycin antimycobacterial antibiotics.
AB - Using the ATP-independent transacylase CapW required for the biosynthesis of capuramycin-type antibiotics, we developed a biocatalytic approach for the synthesis of 43 analogues via a one-step aminolysis reaction from a methyl ester precursor as an acyl donor and various nonnative amines as acyl acceptors. Further examination of the donor substrate scope for CapW revealed that this enzyme can also catalyze a direct transamidation reaction using the major capuramycin congener as a semisynthetic precursor. Biological activity tests revealed that a few of the new capuramycin analogues have significantly improved antibiotic activity against Mycobacterium smegmatis MC2 155 and Mycobacterium tuberculosis H37Rv. Furthermore, most of the analogues are able to be covalently modified by the phosphotransferase CapP/Cpr17 involved in self resistance, providing critical insight for future studies regarding clinical development of the capuramycin antimycobacterial antibiotics.
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U2 - 10.1039/c6ob00381h
DO - 10.1039/c6ob00381h
M3 - Article
C2 - 27050157
AN - SCOPUS:84969216961
SN - 1477-0520
VL - 14
SP - 3956
EP - 3962
JO - Organic and Biomolecular Chemistry
JF - Organic and Biomolecular Chemistry
IS - 16
ER -
