A natural product inspired fragment-based approach towards the development of novel anti-bacterial agents

Austin, Michael J.; Hearnshaw, S.J.; Mitchenall, Lesley A.; McDermott, Paul J.; Howell, Lesley A.; Maxwell, Anthony; Searcey, Mark

doi:10.1039/c6md00229c

Cited by 13 publications

(7 citation statements)

References 28 publications

(25 reference statements)

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Section: New Structures For Old Molecular Targets: “A Good Target Is mentioning

confidence: 99%

“…The coumarin moiety proved necessary for the observed inhibitory activity (IC 50 ~3 µM) of the hybrid compound, which is in part mediated by stabilization of a cleaved-DNA intermediate. 69 The type II fatty acid biosynthetic pathway is an excellent target for antibacterial drug discovery. 70 A Pfizer research group described pyridopyrimidine-based potent biotin carboxylase inhibitors using the FBLG approach.…”

Section: Fragment-based Drug Discoverymentioning

confidence: 99%

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Addressing Antimicrobial Resistance through New Medicinal and Synthetic Chemistry Strategies

Konaklieva

2019

SLAS Discovery

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Over the past century, a multitude of derivatives of structural scaffolds with established antimicrobial potential have been prepared and tested, and a variety of new scaffolds have emerged. The effectiveness of antibiotics, however, is in sharp decline because of the emergence of drug-resistant microorganisms. The prevalence of drug resistance, both in clinical and community settings, is a consequence of bacterial ingenuity in altering pathways and/or cell morphology, making it a persistent threat to human health. The fundamental ability of pathogens to survive in a multitude of habitats can be triggered by recognition of chemical signals that warn organisms of exposure to a potentially harmful environment. Host immune defenses, including reactive oxygen intermediates and antibacterial substances, are among the multitude of chemical signals that can subsequently trigger expression of phenotypes better adapted for survival in that hostile environment. Thus, resistance development appears to be unavoidable, which leads to the conclusion that developing an alternative perspective for treatment options is vital. This review will discuss emerging medicinal chemistry approaches for addressing the global multidrug resistance in the 21st century.

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Section: New Structures For Old Molecular Targets: “A Good Target Is mentioning

confidence: 99%

Section: Fragment-based Drug Discoverymentioning

confidence: 99%

Addressing Antimicrobial Resistance through New Medicinal and Synthetic Chemistry Strategies

Konaklieva

2019

SLAS Discovery

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“…NP-derived fragments can be highly different from synthetic compounds, when structural features, design, and obtention of a library component are compared. (Genis, Kirpichenok, Kombarov, 2012;Austin et al, 2016;Over et al, 2012;Pascolutii et al, 2015;Prescher et al, 2017;Rodrigues et al, 2016).…”

Section: Natural Product-derived Fragmentsmentioning

confidence: 99%

“…Recently, the Searcey group developed a hybrid of the high-molecular weight simocyclinone D8 with ciprofloxacin, using a spacer to link the antibiotic to the coumarin core inspired by the NP structure ( Figure 7). (Austin et al, 2016).…”

Section: B) Natural Product-based Fragmentsmentioning

confidence: 99%

Strategies towards expansion of chemical space of natural product-based compounds to enable drug discovery

Silva

Emery

2018

Braz. J. Pharm. Sci.

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Natural products (NPs) are an excellent source of biologically active molecules that provide many biologically biased features that enable innovative designing of synthetic compounds. NPs are characterized by high content of sp 3-hybridized carbon atoms; oxygen; spiro, bridged, and linked systems; and stereogenic centers, with high structural diversity. To date, several approaches have been implemented for mapping and navigating into the chemical space of NPs to explore the different aspects of chemical space. The approaches providing novel opportunities to synthesize NP-inspired compound libraries involve NP-based fragments and ring distortion strategies. These methodologies allow access to areas of chemical space that are less explored, and consequently help to overcome the limitations in the use of NPs in drug discovery, such as lack of accessibility and synthetic intractability. In this review, we describe how NPs have recently been used as a platform for the development of diverse compounds with high structural and stereochemical complexity. In addition, we show developed strategies aiming to reengineer NPs toward the expansion of NP-based chemical space by fragment-based approaches and chemical degradation to yield novel compounds to enable drug discovery.

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“…To this end, a series of ciprofloxacin-aminocoumarin hybrids has been synthesized, designed to bind to the aminocoumarin pocket of SD8 and to the fluoroquinolone pocket (Austin et al . 2016 ); some of these compounds retain good inhibitory activity against gyrase. It remains to be seen whether such compounds can be developed as viable antibiotics.…”

Section: Simocyclinones As Antibioticsmentioning

confidence: 99%

Structural insights into simocyclinone as an antibiotic, effector ligand and substrate

Buttner

Schäfer

Lawson

et al. 2017

FEMS Microbiology Reviews

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Simocyclinones are antibiotics produced by Streptomyces and Kitasatospora species that inhibit the validated drug target DNA gyrase in a unique way, and they are thus of therapeutic interest. Structural approaches have revealed their mode of action, the inducible-efflux mechanism in the producing organism, and given insight into one step in their biosynthesis. The crystal structures of simocyclinones bound to their target (gyrase), the transcriptional repressor SimR and the biosynthetic enzyme SimC7 reveal fascinating insight into how molecular recognition is achieved with these three unrelated proteins.

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A natural product inspired fragment-based approach towards the development of novel anti-bacterial agents

Cited by 13 publications

References 28 publications

Addressing Antimicrobial Resistance through New Medicinal and Synthetic Chemistry Strategies

Addressing Antimicrobial Resistance through New Medicinal and Synthetic Chemistry Strategies

Strategies towards expansion of chemical space of natural product-based compounds to enable drug discovery

Structural insights into simocyclinone as an antibiotic, effector ligand and substrate

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