Molecular mechanisms of durg inhibition of DNA gyrase

Lewis, Richard J.; Tsai, Francis T.F.; Wigley, Dale B.

doi:10.1002/bies.950180810

Cited by 67 publications

(55 citation statements)

References 65 publications

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“…Antibiotics of the aminocoumarin family exert their therapeutic activity by binding tightly to the B subunit of bacterial DNA gyrase, thereby inhibiting this essential enzyme (19,(24)(25)(26). The toxicity of novobiocin towards eukaryotes, as well as its poor activity towards most gram-negative bacterial pathogens and the proclivity of staphylococci to develop endogenous resistance to aminocoumarins during therapy (14,31), led pharmaceutical companies to direct their antibacterial drug development efforts towards other antibiotic classes, such as ␤-lactams, fluoroquinolones, or macrolides, rather than aminocoumarins (24), even though the efficacy of novobiocin has been confirmed in several recent clinical trials (35,36,40).…”

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“…1) complexed with a 24-kDa fragment of the Escherichia coli DNA gyrase B subunit is that the 5-methyl-1H-pyrrole-2-carboxylate group at the O-3Љ position of L-noviose occupies a hydrophobic pocket and displaces two water molecules that are present when novobiocin (which is carbamoylated at O-3Љ) is complexed with the enzyme. This displacement is regarded as being entropically favorable and is postulated to account for the tighter binding of clorobiocin to DNA gyrase (19). The benzoyl moiety attached to the 3-amino group of the ADHC ring probably contributes weakly to aminocoumarin antibiotic affinity for the B subunit of DNA gyrase through hydrophobic interactions, although it may profoundly influence bacterial aminocoumarin transport (15,18).…”

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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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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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“…Originally, topoisomerase II "catalytic inhibitors" were defined by antibacterial compounds such as novobiocin and coumermycin (12). These coumarin-based drugs block the DNA strand passage activity of the prokaryotic type II enzyme, DNA gyrase, by interfering with the ability of the enzyme to bind its ATP cofactor (13)(14)(15)(16)(17).…”

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Merbarone Inhibits the Catalytic Activity of Human Topoisomerase IIα by Blocking DNA Cleavage

Fortune¹,

Osheroff²

1998

Journal of Biological Chemistry

256

241

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Merbarone is a catalytic inhibitor of topoisomerase II that is in clinical trials as an anticancer agent. Despite the potential therapeutic value of this drug, the mechanism by which it blocks topoisomerase II activity has not been delineated. Therefore, to determine the mechanistic basis for the inhibitory action of merbarone, the effects of this drug on individual steps of the catalytic cycle of human topoisomerase II␣ were assessed. Concentrations of merbarone that inhibited catalytic activity >80% had no effect on either enzyme⅐DNA binding or ATP hydrolysis. In contrast, the drug was a potent inhibitor of enzyme-mediated DNA scission (in the absence or presence of ATP), and the inhibitory profiles of merbarone for DNA cleavage and relaxation were similar. These data indicate that merbarone acts primarily by blocking topoisomerase II-mediated DNA cleavage. Merbarone inhibited DNA scission in a global (rather than site-specific) fashion but did not appear to intercalate into DNA or bind in the minor groove. Since the drug competed with etoposide (a cleavage-enhancing agent that binds directly to topoisomerase II), it is proposed that merbarone exerts its inhibitory effects through interactions with the enzyme and that the drug shares an interaction domain on topoisomerase II with cleavage-enhancing agents.Topoisomerase II is the target for some of the most active anticancer drugs used in the treatment of human malignancies (1-6). Among the topoisomerase II-targeted agents currently in clinical use are etoposide, teniposide, doxorubicin, mitoxantrone, and amsacrine. These drugs kill cells in an unusual fashion. Rather than inhibiting the overall catalytic activity of the type II enzyme, they act by increasing levels of topoisomerase II-mediated DNA cleavage, thus converting this essential enzyme into a potent cellular toxin (1, 3, 5, 7-10). Hence, to distinguish their unique mechanism of action, they are referred to as topoisomerase II "poisons" (11).A second class of drugs that affect the activity of topoisomerase II also appears to have clinical potential (2, 5, 7). In contrast to poisons, these agents act by inhibiting the catalytic activity of the enzyme and display no ability to stimulate DNA cleavage. Originally, topoisomerase II "catalytic inhibitors" were defined by antibacterial compounds such as novobiocin and coumermycin (12). These coumarin-based drugs block the DNA strand passage activity of the prokaryotic type II enzyme, DNA gyrase, by interfering with the ability of the enzyme to bind its ATP cofactor (13-17).Recently, catalytic inhibitors that display high activity against eukaryotic type II topoisomerases have been described. These are typified by drugs such as merbarone (18), aclarubicin (20), fostriecin (21), staurosporine (22), and mitindomide (23), which reflect a variety of inhibitory mechanisms. Aclarubicin, for example, blocks binding of the enzyme to its DNA substrate, the initial step of the topoisomerase II catalytic cycle (24) (see Fig. 12). In contrast, ICRF-193 blocks the final s...

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“…Fluoroquinolones are antibacterial agents that target DNA gyrase (the prokaryotic type II topoisomerase) (9), whereas a variety of DNAintercalating agents such as anthracyclines, amsacrine, and mitoxantrone and nonintercalating agents such as the epipodophyllotoxin etoposide (VP-16) are active against eukaryotic top2 and are clinically important anti-cancer agents (5)(6)(7)(8). Azatoxin is also a nonintercalative top2 poison (10).…”

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Mutation of a Conserved Serine Residue in a Quinolone-resistant Type II Topoisomerase Alters the Enzyme-DNA and Drug Interactions

Strumberg

Nitiss²,

Rose³

et al. 1999

Journal of Biological Chemistry

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A Ser740 3 Trp mutation in yeast topoisomerase II (top2) and of the equivalent Ser 83 in gyrase results in resistance to quinolones and confers hypersensitivity to etoposide (VP-16). We characterized the cleavage complexes induced by the top2 S740W in the human c-myc gene. In addition to resistance to the fluoroquinolone CP-115,953, top2 S740W induced novel DNA cleavage sites in the presence of VP-16, azatoxin, amsacrine, and mitoxantrone. Analysis of the VP-16 sites indicated that the changes in the cleavage pattern were reflected by alterations in base preference. C at position ؊2 and G at position ؉6 were observed for the top2 S740W in addition to the previously reported C؊1 and G؉5 for the wildtype top2. The VP-16-induced top2 S740W cleavage complexes were also more stable. The most stable sites had strong preference for C؊1, whereas the most reversible sites showed no base preference at positions ؊1 or ؊2. Different patterns of DNA cleavage were also observed in the absence of drug and in the presence of calcium. These results indicate that the Ser 740 3 Trp mutation alters the DNA recognition of top2, enhances its DNA binding, and markedly affects its interactions with inhibitors. Thus, residue 740 of top2 appears critical for both DNA and drug interactions.DNA topoisomerases are enzymes that catalyze changes in the topology of DNA via a mechanism involving the transient breakage and rejoining of phosphodiester bonds in the DNA backbone (1). Studies in both prokaryotic and eukaryotic cells have demonstrated the importance of topoisomerases in transcription, DNA replication, and chromosome segregation. The type II topoisomerases, which make transient double-strand breaks and change the linking number of DNA in steps of two, play key roles in chromosome structure. In eukaryotic cells, these enzymes are essential for chromosome condensation/decondensation and decatenation of chromosome loops during mitosis (2, 3).Topoisomerase II (top2) 1 has also been identified as a major target of chemotherapeutic agents that are specifically active against prokaryotic (4) or cancer cells (5-8). Fluoroquinolones are antibacterial agents that target DNA gyrase (the prokaryotic type II topoisomerase) (9), whereas a variety of DNAintercalating agents such as anthracyclines, amsacrine, and mitoxantrone and nonintercalating agents such as the epipodophyllotoxin etoposide (VP-16) are active against eukaryotic top2 and are clinically important anti-cancer agents (5-8).Azatoxin is also a nonintercalative top2 poison (10).Recently, it has been shown that 6,8-difluoro-7-(4Ј-hydroxyphenyl)-1-cyclopropyl-4-quinolone-3-carboxylic acid (CP-115, 953), a fluoroquinolone closely related to ciprofloxacin, is highly toxic to mammalian cells in culture (11,12). Studies in yeast demonstrated that top2 is the primary physiological target for this quinolone (13). Unlike etoposide, which stabilizes top2-mediated DNA cleavage primarily by inhibiting the religation reaction of top2, CP-115,953 stabilizes DNA cleavage by enhancing the forward rate o...

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Molecular mechanisms of durg inhibition of DNA gyrase

Cited by 67 publications

References 65 publications

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

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

Merbarone Inhibits the Catalytic Activity of Human Topoisomerase IIα by Blocking DNA Cleavage

Mutation of a Conserved Serine Residue in a Quinolone-resistant Type II Topoisomerase Alters the Enzyme-DNA and Drug Interactions

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