Improved antibacterial activities of coumarin antibiotics bearing 5′,5′-dialkylnoviose: biological activity of RU79115

Musicki, Branislav; Periers, Anne-Marie; Laurin, Patrick; Ferroud, Didier; Benedetti, Yannick; Lachaud, Sylvette; Chatreaux, Fabienne; Haesslein, Jean‐Luc; Iltis, Alain; Pierre, Christine; Khider, Jean; Tessot, Nicole; Airault, Marlene; Demassey, Jacques; Dupuis‐Hamelin, Claudine; Lassaigne, Patrice; Bonnefoy, Alain; Vicat, Pascale; Klich, Michel

doi:10.1016/s0960-894x(00)00304-8

Cited by 115 publications

(64 citation statements)

References 16 publications

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“…When novobiocin binds to gyrase, the carbamoyl group forms a hydrogen bond with an ordered water molecule in the ATP-binding site. In contrast, the larger MePC group of clorobiocin displaces two ordered water molecules from the ATP-binding site (9,17,23).…”

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confidence: 97%

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Structure-Activity Relationships of Aminocoumarin-Type Gyrase and Topoisomerase IV Inhibitors Obtained by Combinatorial Biosynthesis

Flatman

Eustáquio²,

Li³

et al. 2006

Antimicrob Agents Chemother

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Novobiocin and clorobiocin are gyrase inhibitors produced by Streptomyces strains. Structurally, the two compounds differ only by substitution at two positions: CH 3 versus Cl at position 8 of the aminocoumarin ring and carbamoyl versus 5-methyl-pyrrol-2-carbonyl (MePC) at the 3؆-OH of noviose. Using genetic engineering, we generated a series of analogs carrying H, CH 3 , or Cl at 8 and H, carbamoyl, or MePC at 3؆-OH. Comparison of the gyrase inhibitory activities of all nine structural permutations confirmed that acylation of 3؆-OH is essential for activity, with MePC being more effective than carbamoyl. Substitution at 8 further enhanced activity, but the effect of CH 3 or Cl depended on the nature of the acyl group at 3؆: in the presence of carbamoyl at 3؆, CH 3 resulted in higher activity; in the presence of MePC at 3؆, Cl resulted in higher activity. This suggests that the structures of both natural compounds are highly evolved for optimal interaction with gyrase. In a second series of experiments, clorobiocin derivatives with and without the methyl group at 4؆-OH of noviose, and with different positions of the MePC group of noviose, were tested. Again clorobiocin was superior to all of its analogs. The activities of all compounds were also tested against topoisomerase IV (topo IV). Clorobiocin stood out as a remarkably effective topo IV inhibitor. The relative activities of the different compounds toward topo IV showed a pattern similar to that of the relative gyrase-inhibitory activities. This is the first report of a systematic evaluation of a series of aminocoumarins against both gyrase and topo IV. The results give further insight into the structure-activity relationships of aminocoumarin antibiotics.

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confidence: 97%

“…The total synthesis of aminocoumarins is possible but represents a time-consuming multistep procedure (9,17). However, the biosynthetic gene clusters of novobiocin and clorobiocin have been cloned and sequenced from their respective producers, and the functions of most genes contained therein have been elucidated (12).…”

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confidence: 99%

Structure-Activity Relationships of Aminocoumarin-Type Gyrase and Topoisomerase IV Inhibitors Obtained by Combinatorial Biosynthesis

Flatman

Eustáquio²,

Li³

et al. 2006

Antimicrob Agents Chemother

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“…Early investigations on structure-activity relationships among aminocoumarins (10,37) demonstrated that both ADHC and L-noviose are essential for antibacterial activity and that the substituents attached to these fragments have a significant impact on their bioactivities. Structurally modified aminocoumarins have been synthesized and investigated for their bioactivities with respect to that of novobiocin (6,16,17,27,29,30), and enhancement of the bioactivity of aminocoumarins while simultaneously improving their toxicological and pharmacological properties appears to be a realizable goal.…”

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confidence: 99%

Antimicrobial and DNA Gyrase-Inhibitory Activities of Novel Clorobiocin Derivatives Produced by Mutasynthesis

Galm¹,

Heller

Shapiro

et al. 2004

Antimicrob Agents Chemother

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Twenty-eight novel clorobiocin derivatives obtained from mutasynthesis experiments were investigated for their inhibitory activity towards Escherichia coli DNA gyrase and for their antibacterial activities towards clinically relevant gram-positive and gram-negative bacteria in comparison to novobiocin and clorobiocin. Clorobiocin was the most active compound both against E. coli DNA gyrase in vitro and against bacterial growth. All tested modifications of the 3-dimethylallyl-4-hydroxybenzoyl moiety reduced biological activity. The highest activities were shown by compounds containing a hydrophobic alkyl substituent at position 3 of the 4-hydroxybenzoyl moiety. Polar groups in this side chain, especially amide functions, strongly reduced antibacterial activity. Replacement of the alkyl side chain with a halogen atom or a methoxy group at the same position markedly reduced activity. Transfer of the pyrrole carboxylic acid moiety from O-3؆ to O-2؆ of L-noviose moderately reduced activity, whereas the complete absence of the pyrrole carboxylic acid moiety led to a loss of activity. Desclorobiocin derivatives lacking the chlorine atom at C-8 of the 3-amino-4,7-dihydroxycoumarin moiety also showed low activity. Lack of a methyl group at O-4؆ of L-noviose resulted in an inactive compound. From these findings it appears that clorobiocin represents a "highly evolved" structure optimized for bacterial transport and DNA gyrase inhibition.

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“…Musicki et al (114) utilized the x-ray structures of a 24-kDa N-terminal fragment of GyrB to identify a larger hydrophobic region consisting of Val94 and Phe95, where the methyl groups of novobiocin were located. These two amino acids are conserved across twelve Gram-positive strains and in E. coli.…”

Section: Structure-based Lead Optimizationmentioning

confidence: 99%

Leveraging Structural Information for the Discovery of New Drugs: Computational Methods

Nguyen

Wong

Lightstone

2011

Methods in Molecular Biology

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Escalating problems with drug resistance continue to compromise the effectiveness of commercial antibiotics, necessitating the search for novel classes of antimicrobial agents. To circumvent problems with resistance, a multi-target single-pharmacophore approach has been employed to discover inhibitors that maintain a balanced activity against multiple target enzymes. In this chapter we examine the application of computational techniques, in particular, structure-based drug design approaches, to design new dual-targeting antibacterial agents against bacterial topoisomerases.2

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Improved antibacterial activities of coumarin antibiotics bearing 5′,5′-dialkylnoviose: biological activity of RU79115

Cited by 115 publications

References 16 publications

Structure-Activity Relationships of Aminocoumarin-Type Gyrase and Topoisomerase IV Inhibitors Obtained by Combinatorial Biosynthesis

Structure-Activity Relationships of Aminocoumarin-Type Gyrase and Topoisomerase IV Inhibitors Obtained by Combinatorial Biosynthesis

Antimicrobial and DNA Gyrase-Inhibitory Activities of Novel Clorobiocin Derivatives Produced by Mutasynthesis

Leveraging Structural Information for the Discovery of New Drugs: Computational Methods

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