Biosynthesis of clinically used antibiotic fusidic acid and identification of two short-chain dehydrogenase/reductases with converse stereoselectivity.

Abstract 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. Graphical abstract Fusidane-type antibiotics, represented by fusidic acid, helvolic acid and cephalosporin P 1 , are a group of fungi-derived triterpenoid antibiotics. Here, we firstly identified the biosynthetic gene cluster of the clinically used fusidic acid and characterized its full biosynthetic pathway using a combinational biosynthetic approach. Notably, we identified two short-chain dehydrogenase/reductase FusC1 and FusC2 with converse stereoselectivity in 3-ketoreduction. fx1 [ABSTRACT FROM AUTHOR]