The ups and downs of drug discovery: the early history of Fidaxomicin

McAlpine, James B.

doi:10.1038/ja.2016.157

Cited by 16 publications

(10 citation statements)

References 8 publications

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“…Nov [235]. Structure comparisons not only revealed tiacumicin B and clostomicin B 1 to be identical, but also that a third antibiotic, lipiarmycin A3, discovered in 1975 from culture of Actinoplanes deccanensis A/10655, shared the same structure [231,236]. Ultimately, only tiacumicin B went through to further clinical studies.…”

Section: Tiacumicinmentioning

confidence: 99%

“…Nov. AB718C-41 (NRRL 18085) was isolated based on its activity against MRSA. After scaling up the production, six novel compounds were isolated known collectively as the tiacumicins [100,231]. Structure elucidation of the tiacumicins further revealed a shared 18-membered macrolactone, which differed between the analogues based on the types of modification to the macrocyclic ring and the number and esterification pattern of the sugar groups attached.…”

Section: Tiacumicinmentioning

confidence: 99%

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Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

Robertsen

Musiol-Kroll

2019

Antibiotics

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Actinomycetes are remarkable producers of compounds essential for human and veterinary medicine as well as for agriculture. The genomes of those microorganisms possess several sets of genes (biosynthetic gene cluster (BGC)) encoding pathways for the production of the valuable secondary metabolites. A significant proportion of the identified BGCs in actinomycetes encode pathways for the biosynthesis of polyketide compounds, nonribosomal peptides, or hybrid products resulting from the combination of both polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs). The potency of these molecules, in terms of bioactivity, was recognized in the 1940s, and started the “Golden Age” of antimicrobial drug discovery. Since then, several valuable polyketide drugs, such as erythromycin A, tylosin, monensin A, rifamycin, tetracyclines, amphotericin B, and many others were isolated from actinomycetes. This review covers the most relevant actinomycetes-derived polyketide drugs with antimicrobial activity, including anti-fungal agents. We provide an overview of the source of the compounds, structure of the molecules, the biosynthetic principle, bioactivity and mechanisms of action, and the current stage of development. This review emphasizes the importance of actinomycetes-derived antimicrobial polyketides and should serve as a “lexicon”, not only to scientists from the Natural Products field, but also to clinicians and others interested in this topic.

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Section: Tiacumicinmentioning

confidence: 99%

Section: Tiacumicinmentioning

confidence: 99%

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

Robertsen

Musiol-Kroll

2019

Antibiotics

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“…Fidaxomicin ( 1 ) is a natural product possessing an 18‐membered, highly unsaturated macrolactone and is assigned as the first member of a new class of antibiotics . Antibiotic 1 was first isolated in 1972 from an actinobacterium, Actinoplanes deccanensis , found in a soil sample from India .…”

Section: Isolation Structure Elucidation and Biological Activitymentioning

confidence: 99%

Chemistry and Biology of the Clinically Used Macrolactone Antibiotic Fidaxomicin

Dorst

Gademann

2020

Helvetica Chimica Acta

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Fidaxomicin (1, lipiarmycin A3, clostomicin B1, tiacumicin B) constitutes a glycosylated 18-membered macrolactone and is a natural product isolated from various soil bacteria. Since 2011, fidaxomicin is a marketed antibiotic for the treatment of intestine infections caused by C. difficile in the clinic. Its promising in vitro antibacterial properties against resistant S. aureus and M. tuberculosis continue to attract interest. This review article describes the early history of the antibiotic fidaxomicin and highlights recent advances in the field, such as the elucidation of its mode of action and biosynthesis, as well as known derivatives. Furthermore, different synthetic strategies towards the total synthesis of fidaxomicin are summarized.

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“…[10][11][12] To date, the clinical use is limited to the treatment of C. difficile infections, the main cause of hospital acquired diarrhea, against which fidaxomicin was approved by the FDA in 2011. [13][14][15][16][17] Fidaxomicin inhibits RNA polymerase (RNAP) via a new mechanism of action, rendering second generation derivatives thereof particularly attractive. [18][19][20] Resistance development in bacteria accelerated over the last decades and new mechanisms of resistance have emerged, which calls for the development of antibiotics with unique mechanisms of action.…”

Section: Introductionmentioning

confidence: 99%

Novel Fidaxomicin Antibiotics through Site-Selective Catalysis

Dailler¹,

Dorst²,

Schäfle³

et al. 2020

Preprint

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<div><div><div><p>Fidaxomicin (FDX) is a marketed antibiotic for the treatment Clostridium difficile infections (CDI). Although showing interesting antibacterial properties against many Gram-positive bacteria, the application of this antibiotic is currently limited to treatment of CDI. Semisynthetic modifications present a promising strategy to improve its pharmacokinetic properties and also circumvent resistance development by broadening the structural diversity of derivatives. Based on a rational design using a cryo-EM structure analysis, we implemented two strategic site- selective catalytic reactions with a special emphasis to study the role of the carbohydrate units. Site-selective introduction of various ester moieties on the noviose as well as a Tsuji-Trost type rhamnose cleavage allowed the synthesis of novel fidaxomicin analogs with promising antibacterial activities against C. difficile and M. tuberculosis.</p></div></div></div>

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The ups and downs of drug discovery: the early history of Fidaxomicin

Cited by 16 publications

References 8 publications

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

Chemistry and Biology of the Clinically Used Macrolactone Antibiotic Fidaxomicin

Novel Fidaxomicin Antibiotics through Site-Selective Catalysis

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