“…Fusidic acid, helvolic acid and cephalosporin P 1 are the three representative fusidane-type antibiotics, and among them, only fusidic acid are clinically used. Since they have no cross resistance to commonly used antibiotics, chemical derivatization of fusidane-type antibiotics has been extensively carried out aiming at finding more potent analogues7., 8., 9., 10.. Unfortunately, derivatives with stronger activity than fusidic acid have not been found thus far.…”
Section: Discussionmentioning
confidence: 99%
“…As fusidane-type antibiotics are the only known antibiotics that target elongation factor EF-G to inhibit bacterial protein synthesis4., 5., they have no cross-resistance with commonly used antibiotics, which have drawn much attention in the increasing threat of antimicrobial resistance 6 . Fusidane-type antibiotics have been subjected to extensive chemical synthesis and derivatization7., 8., 9., 10., however, more potent analogues than fusidic acid have not been found thus far. Combinational biosynthesis is an alternative approach to generate chemical diversity, which however requires a deep understanding of the biosynthesis of target compounds.Figure 1Representative fusidane-type antibiotics and gene cluster comparison between fusidic acid and helvolic acid.…”
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.
“…Fusidic acid, helvolic acid and cephalosporin P 1 are the three representative fusidane-type antibiotics, and among them, only fusidic acid are clinically used. Since they have no cross resistance to commonly used antibiotics, chemical derivatization of fusidane-type antibiotics has been extensively carried out aiming at finding more potent analogues7., 8., 9., 10.. Unfortunately, derivatives with stronger activity than fusidic acid have not been found thus far.…”
Section: Discussionmentioning
confidence: 99%
“…As fusidane-type antibiotics are the only known antibiotics that target elongation factor EF-G to inhibit bacterial protein synthesis4., 5., they have no cross-resistance with commonly used antibiotics, which have drawn much attention in the increasing threat of antimicrobial resistance 6 . Fusidane-type antibiotics have been subjected to extensive chemical synthesis and derivatization7., 8., 9., 10., however, more potent analogues than fusidic acid have not been found thus far. Combinational biosynthesis is an alternative approach to generate chemical diversity, which however requires a deep understanding of the biosynthesis of target compounds.Figure 1Representative fusidane-type antibiotics and gene cluster comparison between fusidic acid and helvolic acid.…”
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.
“…Subsequently, this group introduced a spiro-cyclopropane system in the delta-17 (20) double bond, and successfully synthesized 17(S),20(S)methano-FA (4) (Figure 2), which exhibited the same activity against several Gram-positive bacteria as FA. This result further showed the importance of the side chains of FA for antimicrobial activity (Duvold et al, 2003).…”
Fusidic acid (FA) is a natural tetracyclic triterpene isolated from fungi, which is clinically used for systemic and local staphylococcal infections, including methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci infections. FA and its derivatives have been shown to possess a wide range of pharmacological activities, including antibacterial, antimalarial, antituberculosis, anticancer, tumor multidrug resistance reversal, anti-inflammation, antifungal, and antiviral activity in vivo and in vitro. The semisynthesis, structural modification and biological activities of FA derivatives have been extensively studied in recent years. This review summarized the biological activities and structure–activity relationship (SAR) of FA in the last two decades. This summary can prove useful information for drug exploration of FA derivatives.
“…Fusidane-type antibiotics have been subjected to extensive chemical derivatization and biotransformation, because of their pharmaceutical prospects, but analogues with more potent activity than fusidic acid have not been found. − Combinational biosynthesis is a powerful supplement to chemical synthesis, in terms of expanding chemical diversity, however, this requires an understanding of the biosynthetic process of target compounds and the promiscuity of biosynthetic enzymes. Early isotope labeling experiments revealed that the biosynthetic precursor of fusidic acid is protostadienol, but further elucidation remained elusive.…”
Fusidane-type antibiotics are a group of triterpenoid
antibiotics.
They include helvolic acid, fusidic acid, and cephalosporin P1, among which fusidic acid has been used clinically. We have
recently elucidated the biosynthesis of helvolic acid and fusidic
acid, which share an early biosynthetic route involving six conserved
enzymes. Here, we report two separate gene clusters for cephalosporin
P1 biosynthesis. One consists of the six conserved genes,
and the other contains three genes encoding a P450 enzyme (CepB4),
an acetyltransferase (CepD2), and a short-chain dehydrogenase/reductase
(CepC2). Introduction of these three genes into Aspergillus
oryzae, which harbors the six conserved genes, produced cephalosporin
P1. Stepwise introduction revealed that CepB4 not only
catalyzes stereoselective dual oxidation of C6 and C7, but also monooxygenation
of C6 or C7. This led to the generation of five new analogues. Using
monohydroxylated products as substrates, we demonstrated that CepD2
specifically acetylates C6-OH, although both C6-OH and C7-OH acetylated
analogues have been identified in nature.
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