The spread of antibiotic-resistant bacteria and exhausted drug leads render some infections untreatable now and in the future.To deal with these“new challenges”,scientists tend to re-pick up“old antibiotics”.Fusid...The spread of antibiotic-resistant bacteria and exhausted drug leads render some infections untreatable now and in the future.To deal with these“new challenges”,scientists tend to re-pick up“old antibiotics”.Fusidane-type antibiotics have been known for nearly 80 years as potent antibacterial agents against gram-positive bacteria,especially Staphylococci,and represent the only triterpene-derived antibiotic class in clinical setting.These attractive characteristics have drawn renewed attention on fusidane-type antibiotics in recent decades.Isolation,characterization,biological evaluation,as well as chemical modifications of fusidane-type antibiotics are increasingly being reported.Combinatorial biosynthesis of this type of antibiotics has been successfully utilized not only for elucidating the biosynthetic pathways,but also for expanding their structural diversity.Some isolated and synthetic compounds exhibit comparable or even more potent biological activity than fusidic acid.This review provides an overview of progress on the studies of structure and biology of fusidane-type antibiotics from 1943 to April 2021.The informative structure-activity relationship is also highlighted.展开更多
Fusidane-type antibiotics,represented by helvolic acid,fusidic acid and cephalosporin P1,are fungi-derived antimicrobials with little cross-resistance to commonly used antibiotics.Generation of new fusidane-type deriv...Fusidane-type antibiotics,represented by helvolic acid,fusidic acid and cephalosporin P1,are fungi-derived antimicrobials with little cross-resistance to commonly used antibiotics.Generation of new fusidane-type derivatives is therefore of great value,but this is hindered by available approaches.Here,we developed a stochastic combinational strategy by random assembly of all the post-tailoring genes derived from helvolic acid,fusidic acid,and cephalosporin P1 biosynthetic pathways in a strain that produces their common intermediate.Among a total of 27 gene combinations,24 combinations produce expected products and afford 58 fusidane-type analogues,of which 54 are new compounds.Moreover,random gene combination can induce unexpected activity of some post-tailoring enzymes,leading to a further increase in chemical diversity.These newly generated derivatives provide new insights into the structure-activity relationship of fusidane-type antibiotics.The stochastic combinational strategy established in this study proves to be a powerful approach for expanding structural diversity of natural products.展开更多
Fusidic acid is the only fusidane-type antibiotic that has been clinically used. However,biosynthesis of this important molecule in fungi is poorly understood. We have recently elucidated the biosynthesis of fusidane-...Fusidic acid is the only fusidane-type antibiotic that has been clinically used. However,biosynthesis of this important molecule in fungi is poorly understood. We have recently elucidated the biosynthesis of fusidane-type antibiotic helvolic acid, which provides us with clues to identify a possible gene cluster for fusidic acid(fus cluster). This gene cluster consists of eight genes, among which six are conserved in the helvolic acid gene cluster except fusC1 and fusB1. Introduction of the two genes into the Aspergillus oryzae NSAR1 expressing the conserved six genes led to the production of fusidic acid. A stepwise introduction of fusC1 and fusB1 revealed that the two genes worked independently without a strict reaction order. Notably, we identified two short-chain dehydrogenase/reductase genes fusC1 and fusC2 in the fus cluster, which showed converse stereoselectivity in 3-ketoreduction. This is the first report on the biosynthesis and heterologous expression of fusidic acid.展开更多
基金supported by the National Natural Science Foundation of China(Nos.81903494 and 81903483)。
文摘The spread of antibiotic-resistant bacteria and exhausted drug leads render some infections untreatable now and in the future.To deal with these“new challenges”,scientists tend to re-pick up“old antibiotics”.Fusidane-type antibiotics have been known for nearly 80 years as potent antibacterial agents against gram-positive bacteria,especially Staphylococci,and represent the only triterpene-derived antibiotic class in clinical setting.These attractive characteristics have drawn renewed attention on fusidane-type antibiotics in recent decades.Isolation,characterization,biological evaluation,as well as chemical modifications of fusidane-type antibiotics are increasingly being reported.Combinatorial biosynthesis of this type of antibiotics has been successfully utilized not only for elucidating the biosynthetic pathways,but also for expanding their structural diversity.Some isolated and synthetic compounds exhibit comparable or even more potent biological activity than fusidic acid.This review provides an overview of progress on the studies of structure and biology of fusidane-type antibiotics from 1943 to April 2021.The informative structure-activity relationship is also highlighted.
基金financially supported by grants from National Key Research and Development Program of China (2018YFA0903200 and 2018YFA0903201)the National Natural Science Foundation of China (31870032, 81925037, 31761143016, 31670036 and 31800021)+8 种基金the 111 Project of Ministry of Education of the People’s Republic of China (B13038)Chang Jiang Scholars Program (Young Scholar) from the Ministry of Education of China (Hao Gao, 2017)National High-level Personnel of Special Support Program (2017RA2259, China)the Guangdong Natural Science Funds for Distinguished Young Scholar (2019B151502014, China)Guangdong Science and Technology Planning Project (2020A0505100041, China)Guangdong Special Support Program (2016TX03R280, China)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y036, China)K. C. Wong Education Foundation (Hao Gao, 2016, China)Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (JSPS KAKENHI Grant Number JP16H06443, JP20KK0173, and JP20H00490)。
文摘Fusidane-type antibiotics,represented by helvolic acid,fusidic acid and cephalosporin P1,are fungi-derived antimicrobials with little cross-resistance to commonly used antibiotics.Generation of new fusidane-type derivatives is therefore of great value,but this is hindered by available approaches.Here,we developed a stochastic combinational strategy by random assembly of all the post-tailoring genes derived from helvolic acid,fusidic acid,and cephalosporin P1 biosynthetic pathways in a strain that produces their common intermediate.Among a total of 27 gene combinations,24 combinations produce expected products and afford 58 fusidane-type analogues,of which 54 are new compounds.Moreover,random gene combination can induce unexpected activity of some post-tailoring enzymes,leading to a further increase in chemical diversity.These newly generated derivatives provide new insights into the structure-activity relationship of fusidane-type antibiotics.The stochastic combinational strategy established in this study proves to be a powerful approach for expanding structural diversity of natural products.
基金supported by grants from the National Natural Science Foundation of China(31870032,3171101305,and 31670036)the 111 Project of Ministry of Education of the People's Republic of China(B13038)+9 种基金the JST/NSFC Strategic International Collaborative Research ProgramJapanese-Chinese Collaborative Research ProgramChang Jiang Scholars Program(Hao Gao,2017)from the Ministry of Education of ChinaGuangdong Special Support Program(2016TX03R280)Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme(Hao Gao,2014)K.C.Wong Education Foundation(Hao Gao,2016)Guangzhou Science and Technology Project(201707010266,China)the Fundamental Research Funds for the Central Universities(21617495)Kobayashi International Scholarship Foundationa Grant-in-Aid for Scientific Research from the Ministry of Education,Culture,Sports,Science and Technology,Japan(JSPS KAKENHI Grant Number JP15H01836 and JP16H06443)
文摘Fusidic acid is the only fusidane-type antibiotic that has been clinically used. However,biosynthesis of this important molecule in fungi is poorly understood. We have recently elucidated the biosynthesis of fusidane-type antibiotic helvolic acid, which provides us with clues to identify a possible gene cluster for fusidic acid(fus cluster). This gene cluster consists of eight genes, among which six are conserved in the helvolic acid gene cluster except fusC1 and fusB1. Introduction of the two genes into the Aspergillus oryzae NSAR1 expressing the conserved six genes led to the production of fusidic acid. A stepwise introduction of fusC1 and fusB1 revealed that the two genes worked independently without a strict reaction order. Notably, we identified two short-chain dehydrogenase/reductase genes fusC1 and fusC2 in the fus cluster, which showed converse stereoselectivity in 3-ketoreduction. This is the first report on the biosynthesis and heterologous expression of fusidic acid.
