Total Synthesis of Desmethyl Macrolide Antibiotics

Andrade, Rodrigo

doi:10.1055/s-0034-1381047

Cited by 17 publications

(16 citation statements)

References 42 publications

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“…115 The results of these assays are summarized in Table 2. Against the Gram-positive S. aureus , all compounds, including telithromycin, were ineffective.…”

Section: Macrolides and Ketolides–from Fermentation To Synthesismentioning

confidence: 99%

Natural Products as Platforms To Overcome Antibiotic Resistance

2017

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Natural products have served as powerful therapeutics against pathogenic bacteria since the golden age of antibiotics of the mid-20th century. However, the increasing frequency of antibiotic-resistant infections clearly demonstrates that new antibiotics are critical for modern medicine. Because combinatorial approaches have not yielded effective drugs, we propose that the development of new antibiotics around proven natural scaffolds is the best short-term solution to the rising crisis of antibiotic resistance. We analyze herein synthetic approaches aiming to reengineer natural products into potent antibiotics. Furthermore, we discuss approaches in modulating quorum sensing and biofilm formation as a nonlethal method, as well as narrowspectrum pathogen-specific antibiotics, which are of interest given new insights into the implications of disrupting the microbiome.

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“…115 The results of these assays are summarized in Table 2. Against the Gram-positive S. aureus , all compounds, including telithromycin, were ineffective.…”

Section: Macrolides and Ketolides–from Fermentation To Synthesismentioning

confidence: 99%

Natural Products as Platforms To Overcome Antibiotic Resistance

2017

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“…Eight simple building blocks (1)(2)(3)(4)(5)(6)(7)(8), two of which are commercially available and six of which are synthesized in sequences of 3-6 steps in 30-150-g amounts, are assembled in a highly convergent manner (Fig. 2).…”

Section: Synthesis Of 14-membered Azaketolidesmentioning

confidence: 99%

“…Macrolide antibiotics (macrocyclic lactones with one or more pendant glycosidic residues), which have proven to be safe and effective for use in treating human infectious diseases such as community-acquired bacterial pneumonia, gonorrhoea and others, provide a compelling case in point. Since the discovery of erythromycin from a Philippine soil sample in 1949 4 , in spite of extraordinary efforts leading to fully synthetic [5][6][7][8] and modified biosynthetic routes [9][10][11][12] to macrolide antibiotics, all members of this class approved or in clinical development for use in humans have been manufactured by chemically modifying erythromycin (erythromycin itself is unstable in the stomach, and rearranges to form a product with gastrointestinal side-effects) 13 . Thus, azithromycin is prepared from erythromycin in four steps 14 , clarithromycin requires six steps 15 , and the advanced clinical candidate solithromycin is currently produced from erythromycin by a 16-step linear sequence ( Fig.…”

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confidence: 99%

A platform for the discovery of new macrolide antibiotics

Seiple

Zhang

Jakubec

et al. 2016

Nature

297

214

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The chemical modification of structurally complex fermentation products, a process known as semisynthesis, has been an important tool in the discovery and manufacture of antibiotics for the treatment of various infectious diseases. However, many of the therapeutics obtained in this way are no longer effective, because bacterial resistance to these compounds has developed. Here we present a practical, fully synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building blocks, enabling the synthesis of diverse structures not accessible by traditional semisynthetic approaches. More than 300 new macrolide antibiotic candidates, as well as the clinical candidate solithromycin, have been synthesized using our convergent approach. Evaluation of these compounds against a panel of pathogenic bacteria revealed that the majority of these structures had antibiotic activity, some efficacious against strains resistant to macrolides in current use. The chemistry we describe here provides a platform for the discovery of new macrolide antibiotics and may also serve as the basis for their manufacture.

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“…20 On the basis of these prior reports, we sought to evaluate fully all desilyated compounds en route to “carylacton” to understand better the SAR of such perturbations. We envisioned three logical branching points that would facilitate the production of four distinct scaffolds whereby we could evaluate the role that the acetonide, olefin, and oxidation state play in bioactivity.…”

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confidence: 99%

Diverted Total Synthesis of Carolacton-Inspired Analogs Yields Three Distinct Phenotypes in Streptococcus mutans Biofilms

et al. 2017

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The oral microbiome is a dynamic environment inhabited by both commensals and pathogens. Among these is Streptococcus mutans, the causative agent of dental caries, the most prevalent childhood disease. Carolacton has remarkably specific activity against S. mutans, causing acid-mediated cell death during biofilm formation; however, its complex structure limits its utility. Herein, we report the diverted total synthesis and biological evaluation of a rationally designed library of simplified analogs that unveiled three unique biofilm phenotypes further validating the role of natural product synthesis in the discovery of new biological phenomena.

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Total Synthesis of Desmethyl Macrolide Antibiotics

Cited by 17 publications

References 42 publications

Natural Products as Platforms To Overcome Antibiotic Resistance

Natural Products as Platforms To Overcome Antibiotic Resistance

A platform for the discovery of new macrolide antibiotics

Diverted Total Synthesis of Carolacton-Inspired Analogs Yields Three Distinct Phenotypes in Streptococcus mutans Biofilms

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