TY - JOUR
T1 - Bioactivity-HiTES Unveils Cryptic Antibiotics Encoded in Actinomycete Bacteria
AU - Moon, Kyuho
AU - Xu, Fei
AU - Zhang, Chen
AU - Seyedsayamdost, Mohammad R.
N1 - Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/4/19
Y1 - 2019/4/19
N2 - Bacteria harbor an immense reservoir of potentially new and therapeutic small molecules in the form of "silent" biosynthetic gene clusters (BGCs). These BGCs can be identified bioinformatically but are sparingly expressed under normal laboratory growth conditions, or not at all, and therefore do not produce significant levels of the corresponding small molecule product. Several methods have been developed for activating silent BGCs. A major limitation for nearly all methods is that they require genetic procedures and/or do not report on the bioactivity of the cryptic metabolite. We herein report "Bioactivty-HiTES", an approach that links the bioactivity of cryptic metabolites to their induction while at the same time obviating the need for genetic manipulations. Using this method, we detected induction of cryptic antibiotics in three actinomycete strains that were tested. Follow-up studies in one case allowed us to structurally elucidate two cryptic metabolites, elicited by the β-blocker atenolol in Streptomyces hiroshimensis, with selective growth-inhibitory activity against Gram-negative bacteria, notably Escherichia coli and Acinetobacter baumannii. Atenolol turned out to be a global elicitor of secondary metabolism, and characterization of additional cryptic metabolites led to the discovery of a novel naphthoquinone epoxide. Bioactivity-HiTES is a general, widely applicable procedure that will be useful in identifying cryptic bioactive metabolites in the future.
AB - Bacteria harbor an immense reservoir of potentially new and therapeutic small molecules in the form of "silent" biosynthetic gene clusters (BGCs). These BGCs can be identified bioinformatically but are sparingly expressed under normal laboratory growth conditions, or not at all, and therefore do not produce significant levels of the corresponding small molecule product. Several methods have been developed for activating silent BGCs. A major limitation for nearly all methods is that they require genetic procedures and/or do not report on the bioactivity of the cryptic metabolite. We herein report "Bioactivty-HiTES", an approach that links the bioactivity of cryptic metabolites to their induction while at the same time obviating the need for genetic manipulations. Using this method, we detected induction of cryptic antibiotics in three actinomycete strains that were tested. Follow-up studies in one case allowed us to structurally elucidate two cryptic metabolites, elicited by the β-blocker atenolol in Streptomyces hiroshimensis, with selective growth-inhibitory activity against Gram-negative bacteria, notably Escherichia coli and Acinetobacter baumannii. Atenolol turned out to be a global elicitor of secondary metabolism, and characterization of additional cryptic metabolites led to the discovery of a novel naphthoquinone epoxide. Bioactivity-HiTES is a general, widely applicable procedure that will be useful in identifying cryptic bioactive metabolites in the future.
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U2 - 10.1021/acschembio.9b00049
DO - 10.1021/acschembio.9b00049
M3 - Article
C2 - 30830740
AN - SCOPUS:85063576992
SN - 1554-8929
VL - 14
SP - 767
EP - 774
JO - ACS chemical biology
JF - ACS chemical biology
IS - 4
ER -