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

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.

Determination of Fusidic Acid Susceptibility of Multidrug-resistant Gonococcal Isolates from China

The currently recommended gonococcal therapies are rapidly losing efficacy and;therefore,novel options for treatment are urgently required to ensure future treatment remains available.Here we investigated the susceptibility of 379 contemporary clinical Neisseria gonorrhoeae isolates from China for susceptibility to fusidic acid.These isolates include numerous multidrug-resistant strains with resistance or reduced susceptibility against ceftriaxone and/or azithromycin,antimicrobials that are currently recommended as a first-line dual therapy.Although official susceptibility breakpoints have not been established,all gonococcal isolates appeared to be susceptible to fusidic acid,with the majority of isolates displaying a minimal inhibitory concentration(MIC)of 0.25 or 0.5mg/L.Overall,the MIC90 was 0.5mg/L,with a MIC range of 0.08-2mg/L.Importantly,no correlation between fusidic acid susceptibility and susceptibility to ceftriaxone or azithromycin was observed.Further analysis of gonococcal survival curves indicated that fusidic acid was only mildly bactericidal at the highest tested concentrations(4
MIC).In conclusion,fusidic acid displayed consistent antimicrobial activity against N.gonorrhoeae and,given the absence of cross-resistance with ceftriaxone and azithromycin,might be interesting for further evaluation of single or dual antimicrobial therapies in combination with ceftriaxone or azithromycin.

Meta-analysis of the efficacy and safety of sodium fusidate ointment and mupirocin ointment in the treatment of bacteria-infected skin disease

Objective:To evaluate the efficacy and safety of sodium fusidate ointment and mupirocin ointment in the treatment of bacteria-infected skin disease.Methods:The search terms“sodium fusidate ointment”,“mupirocin ointment”,“bacterial infection”,etc.were searched in the database of PubMed,EMbase,Cochrane,Web of Science,Wanfang,VIP,and CNKI.The search time was from inception to November 2019.Randomized controlled trials of sodium fusidate ointment and mupirocin ointment for the treatment of bacteria-infected skin disease were collected.Two studies independently performed literature screening,data extraction,and literature quality evaluation.Meta analysis was performed using RevMan 5.3 software.Results:A total of 14 literature were included,involving 1,825 patients,916 in the experimental group,and 909 in the control group.Meta analysis results showed that the total clinical effective rate of the experimental group(RR=1.12,95%CI(1.06,1.19),P<0.0001),degree of improvement in pruritus score(MD=−1.21,95%CI(−1.78,−0.64),P<0.0001),degree of improvement of eczema area and severity index score(MD=−2.47,95%CI(−3.92,−1.02),P=0.0008),and sensitivity rate of drug sensitivity test(RR=1.35,95%CI(1.24,1.46),P<0.00001)were better than those of control group.The incidence of adverse reactions(RR=0.18,95%CI(0.09,0.39),P<0.00001)was significantly smaller than that of control group.But the bacterial clearance rate(RR=1.22,95%CI(0.98,1.52),P=0.08)compared with the control group,the difference was not statistically significant.Conclusion:Sodium fusidate ointment is better than mupirocin ointment in the treatment of bacteria-infected skin disease,and it helps to improve the severity of disease and itching,and has good safety,which is worthy of clinical promotion.

Old fusidane-type antibiotics for new challenges:Chemistry and biology

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.