Novel Bacterial Type II Topoisomerase Inhibitors

Abstract With the diminishing effectiveness of current antibacterial therapies, it is critically important to discover agents that operate by a mechanism that circumvents existing resistance. ETX0914, the first of a new class of antibacterial agent targeted for the treatment of gonorrhea, operates by a novel mode-of-inhibition against bacterial type II topoisomerases. Incorporating an oxazolidinone on the scaffold mitigated toxicological issues often seen with topoisomerase inhibitors. Organisms resistant to other topoisomerase inhibitors were not cross-resistant with ETX0914 nor were spontaneous resistant mutants to ETX0914 cross-resistant with other topoisomerase inhibitor classes, including the widely used fluoroquinolone class. Preclinical evaluation of ETX0914 pharmacokinetics and pharmacodynamics showed distribution into vascular tissues and efficacy in a murine Staphylococcus aureus infection model that served as a surrogate for predicting efficacious exposures for the treatment of Neisseria gonorrhoeae infections. A wide safety margin to the efficacious exposure in toxicological evaluations supported progression to Phase 1. Dosing ETX0914 in human volunteers showed sufficient exposure and minimal adverse effects to expect a highly efficacious anti-gonorrhea therapy.

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Correction to Discovery and Optimization of Indolyl-Containing 4-Hydroxy-2-pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-Negative Bacteria

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.8b01538 ◽

2018 ◽

Vol 61 (20) ◽

pp. 9394-9394

Author(s):

Aleksey I. Gerasyuto ◽

Michael A. Arnold ◽

Jiashi Wang ◽

Guangming Chen ◽

Xiaoyan Zhang ◽

...

Keyword(s):

Multidrug Resistant ◽

Gram Negative Bacteria ◽

Type Ii ◽

Topoisomerase Inhibitors ◽

Dna Topoisomerase ◽

Gram Negative

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Engineered Biosynthesis of a Novel Amidated Polyketide, Using the Malonamyl-Specific Initiation Module from the Oxytetracycline Polyketide Synthase

Applied and Environmental Microbiology ◽

10.1128/aem.72.4.2573-2580.2006 ◽

2006 ◽

Vol 72 (4) ◽

pp. 2573-2580 ◽

Cited By ~ 83

Author(s):

Wenjun Zhang ◽

Brian D. Ames ◽

Shiou-Chuan Tsai ◽

Yi Tang

Keyword(s):

Polyketide Synthase ◽

Major Product ◽

Polyketide Synthases ◽

Type Ii ◽

Streptomyces Rimosus ◽

Aromatic Polyketides ◽

Starter Unit ◽

Necessary And Sufficient ◽

Bacterial Type

ABSTRACT Tetracyclines are aromatic polyketides biosynthesized by bacterial type II polyketide synthases (PKSs). Understanding the biochemistry of tetracycline PKSs is an important step toward the rational and combinatorial manipulation of tetracycline biosynthesis. To this end, we have sequenced the gene cluster of oxytetracycline (oxy and otc genes) PKS genes from Streptomyces rimosus. Sequence analysis revealed a total of 21 genes between the otrA and otrB resistance genes. We hypothesized that an amidotransferase, OxyD, synthesizes the malonamate starter unit that is a universal building block for tetracycline compounds. In vivo reconstitution using strain CH999 revealed that the minimal PKS and OxyD are necessary and sufficient for the biosynthesis of amidated polyketides. A novel alkaloid (WJ35, or compound 2) was synthesized as the major product when the oxy-encoded minimal PKS, the C-9 ketoreductase (OxyJ), and OxyD were coexpressed in CH999. WJ35 is an isoquinolone compound derived from an amidated decaketide backbone and cyclized with novel regioselectivity. The expression of OxyD with a heterologous minimal PKS did not afford similarly amidated polyketides, suggesting that the oxy-encoded minimal PKS possesses novel starter unit specificity.

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Inhibitory Activities of Gatifloxacin (AM-1155), a Newly Developed Fluoroquinolone, against Bacterial and Mammalian Type II Topoisomerases

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.10.2678 ◽

1998 ◽

Vol 42 (10) ◽

pp. 2678-2681 ◽

Cited By ~ 22

Author(s):

Masaya Takei ◽

Hideyuki Fukuda ◽

Tokutaro Yasue ◽

Masaki Hosaka ◽

Yasuo Oomori

Keyword(s):

Hela Cell ◽

Topoisomerase Ii ◽

Dna Gyrase ◽

Antibacterial Activities ◽

Type Ii ◽

Topoisomerase Iv ◽

E Coli ◽

Bacterial Enzyme ◽

Inhibitory Activities ◽

Bacterial Type

ABSTRACT We determined the inhibitory activities of gatifloxacin againstStaphylococcus aureus topoisomerase IV,Escherichia coli DNA gyrase, and HeLa cell topoisomerase II and compared them with those of several quinolones. The inhibitory activities of quinolones against these type II topoisomerases significantly correlated with their antibacterial activities or cytotoxicities (correlation coefficient [r] = 0.926 forS. aureus, r = 0.972 for E. coli, and r = 0.648 for HeLa cells). Gatifloxacin possessed potent inhibitory activities against bacterial type II topoisomerases (50% inhibitory concentration [IC50] = 13.8 μg/ml for S. aureustopoisomerase IV; IC50 = 0.109 μg/ml for E. coli DNA gyrase) but the lowest activity against HeLa cell topoisomerase II (IC50 = 265 μg/ml) among the quinolones tested. There was also a significant correlation between the inhibitory activities of quinolones against S. aureustopoisomerase IV and those against E. coli DNA gyrase (r = 0.969). However, the inhibitory activity against HeLa cell topoisomerase II did not correlate with that against either bacterial enzyme. The IC50 of gatifloxacin for HeLa cell topoisomerase II was 19 and was more than 2,400 times higher than that for S. aureus topoisomerase IV and that for E. coli DNA gyrase. These ratios were higher than those for other quinolones, indicating that gatifloxacin possesses a higher selectivity for bacterial type II topoisomerases.

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