Design, Synthesis, and Biological Evaluation of Hexacyclic Tetracyclines as Potent, Broad Spectrum Antibacterial Agents

Sun, Cuixiang; Hunt, Diana K.; Chen, Chi-Li; Deng, Yuqi; He, Minsheng; Clark, Roger B.; Fyfe, Corey; Grossman, Trudy H.; Sutcliffe, Joyce A.; Xiao, Xiao-Yi

doi:10.1021/acs.jmedchem.5b00262

Cited by 17 publications

(19 citation statements)

References 20 publications

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“…Of all the compounds studied, the best results were recorded for C7-fluorohexacycline and C7-trifluoromethoxyhexacycline, with a broad antibacterial activity in vitro and good activity in vivo on Pseudomonas aeruginosa. The promising data extracted from this study support the optimisation of this type of skeleton to discover and obtain in the future some new tetracyclines that are clinically valuable [182].…”

Section: New Compounds Under Developmentmentioning

confidence: 58%

The Development of Third-Generation Tetracycline Antibiotics and New Perspectives

Rusu

Buta

2021

Pharmaceutics

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The tetracycline antibiotic class has acquired new valuable members due to the optimisation of the chemical structure. The first modern tetracycline introduced into therapy was tigecycline, followed by omadacycline, eravacycline, and sarecycline (the third generation). Structural and physicochemical key elements which led to the discovery of modern tetracyclines are approached. Thus, several chemical subgroups are distinguished, such as glycylcyclines, aminomethylcyclines, and fluorocyclines, which have excellent development potential. The antibacterial spectrum comprises several resistant bacteria, including those resistant to old tetracyclines. Sarecycline, a narrow-spectrum tetracycline, is notable for being very effective against Cutinebacterium acnes. The mechanism of antibacterial action from the perspective of the new compound is approached. Several severe bacterial infections are treated with tigecycline, omadacycline, and eravacycline (with parenteral or oral formulations). In addition, sarecycline is very useful in treating acne vulgaris. Tetracyclines also have other non-antibiotic properties that require in-depth studies, such as the anti-inflammatory effect effect of sarecycline. The main side effects of modern tetracyclines are described in accordance with published clinical studies. Undoubtedly, this class of antibiotics continues to arouse the interest of researchers. As a result, new derivatives are developed and studied primarily for the antibiotic effect and other biological effects.

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Section: New Compounds Under Developmentmentioning

confidence: 58%

The Development of Third-Generation Tetracycline Antibiotics and New Perspectives

Rusu

Buta

2021

Pharmaceutics

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“…More recently, a fully synthetic chemistry approach has led to the discovery of eravacycline, which shows promise in the treatment of serious infections caused by a broad range of bacterial pathogens. Ongoing exploration of synthetic tetracycline derivatives has enabled improvements in potency against P. aeruginosa and other difficult-to-treat MDR Gram-negative pathogens (Deng et al 2012;O'Brien et al 2012;Xiao et al 2013;Grossman et al 2014a;Sun et al 2014aSun et al , 2015. The ability to synthesize completely novel, "unnatural" tetracyclines opens new opportunities to more fully explore the potential of this familiar and clinically validated antibiotic class.…”

Section: Resultsmentioning

confidence: 99%

Tetracycline Antibiotics and Resistance

Grossman

2016

Cold Spring Harb Perspect Med

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490

345

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“…156 More recently, the Myers group published a modified synthetic route to 5-oxytetracycline derivatives, which were hypothesized to enhance activity against Gram-negative strains thanks to an increase in polar surface area. 157 However, these compounds did not show an increase in potency, which might be attributed to poor aqueous stability.…”

Section: From Benchtop To Bedside—innovations In the Tetracyclinesmentioning

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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Design, Synthesis, and Biological Evaluation of Hexacyclic Tetracyclines as Potent, Broad Spectrum Antibacterial Agents

Cited by 17 publications

References 20 publications

The Development of Third-Generation Tetracycline Antibiotics and New Perspectives

The Development of Third-Generation Tetracycline Antibiotics and New Perspectives

Tetracycline Antibiotics and Resistance

Natural Products as Platforms To Overcome Antibiotic Resistance

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