scholarly journals Erratum: Corrigendum: Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Gregory S. Basarab ◽  
Gunther H. Kern ◽  
John McNulty ◽  
John P. Mueller ◽  
Kenneth Lawrence ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Type Ii ◽  
Distinct Mechanism ◽  
Bacterial Type

scholarly journals Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Gregory S. Basarab ◽  
Gunther H. Kern ◽  
John McNulty ◽  
John P. Mueller ◽  
Kenneth Lawrence ◽  
...  
Keyword(s):  
Phase 1 ◽  
Safety Margin ◽  
Infection Model ◽  
Type Ii ◽  
Topoisomerase Inhibitors ◽  
Pharmacokinetics And Pharmacodynamics ◽  
New Class ◽  
Distinct Mechanism ◽  
Human Volunteers ◽  
Bacterial Type

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.

scholarly journals The Phosphoenolpyruvate:Sugar Phosphotransferase System Is Involved in Sensitivity to the Glucosylated Bacteriocin Sublancin

2015 ◽  
Vol 59 (11) ◽  
pp. 6844-6854 ◽  
Author(s):  
C. V. Garcia De Gonzalo ◽  
E. L. Denham ◽  
R. A. T. Mars ◽  
J. Stülke ◽  
W. A. van der Donk ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Mechanism Of Action ◽  
Mode Of Action ◽  
Phosphotransferase System ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Distinct Mechanism ◽  
Genomic Studies ◽  
Increased Sensitivity ◽  
Bacterial Sensitivity

ABSTRACTThe mode of action of a group of glycosylated antimicrobial peptides known as glycocins remains to be elucidated. In the current study of one glycocin, sublancin, we identified the phosphoenolpyruvate:sugar phosphotransferase system (PTS) ofBacillusspecies as a key player in bacterial sensitivity. Sublancin kills several Gram-positive bacteria, such asBacillusspecies andStaphylococcus aureus, including methicillin-resistantS. aureus(MRSA). Unlike other classes of bacteriocins for which the PTS is involved in their mechanism of action, we show that the addition of PTS-requiring sugars leads to increased resistance rather than increased sensitivity, suggesting that sublancin has a distinct mechanism of action. Collectively, our present mutagenesis and genomic studies demonstrate that the histidine-containing phosphocarrier protein (HPr) and domain A of enzyme II (PtsG) in particular are critical determinants for bacterial sensitivity to sublancin.

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

2006 ◽  
Vol 72 (4) ◽  
pp. 2573-2580 ◽  
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.

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

1998 ◽  
Vol 42 (10) ◽  
pp. 2678-2681 ◽  
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.

Synthesis and Antimicrobial Activity of 4-Chloro-3-Nitrophenylthiourea Derivatives Targeting Bacterial Type II Topoisomerases

2016 ◽  
Vol 87 (6) ◽  
pp. 905-917 ◽  
Author(s):  
Anna Bielenica ◽  
Karolina Stępień ◽  
Agnieszka Napiórkowska ◽  
Ewa Augustynowicz-Kopeć ◽  
Sylwester Krukowski ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Type Ii ◽  
Bacterial Type

scholarly journals Structural and functional analysis of two di-domain aromatase/cyclases from type II polyketide synthases

2015 ◽  
Vol 112 (50) ◽  
pp. E6844-E6851 ◽  
Author(s):  
Grace Caldara-Festin ◽  
David R. Jackson ◽  
Jesus F. Barajas ◽  
Timothy R. Valentic ◽  
Avinash B. Patel ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Functional Role ◽  
Functional Characterization ◽  
Polyketide Synthases ◽  
Type Ii ◽  
Aromatic Polyketides ◽  
Linear Poly ◽  
Bacterial Type

Aromatic polyketides make up a large class of natural products with diverse bioactivity. During biosynthesis, linear poly-β-ketone intermediates are regiospecifically cyclized, yielding molecules with defined cyclization patterns that are crucial for polyketide bioactivity. The aromatase/cyclases (ARO/CYCs) are responsible for regiospecific cyclization of bacterial polyketides. The two most common cyclization patterns are C7–C12 and C9–C14 cyclizations. We have previously characterized three monodomain ARO/CYCs: ZhuI, TcmN, and WhiE. The last remaining uncharacterized class of ARO/CYCs is the di-domain ARO/CYCs, which catalyze C7–C12 cyclization and/or aromatization. Di-domain ARO/CYCs can further be separated into two subclasses: “nonreducing” ARO/CYCs, which act on nonreduced poly-β-ketones, and “reducing” ARO/CYCs, which act on cyclized C9 reduced poly-β-ketones. For years, the functional role of each domain in cyclization and aromatization for di-domain ARO/CYCs has remained a mystery. Here we present what is to our knowledge the first structural and functional analysis, along with an in-depth comparison, of the nonreducing (StfQ) and reducing (BexL) di-domain ARO/CYCs. This work completes the structural and functional characterization of mono- and di-domain ARO/CYCs in bacterial type II polyketide synthases and lays the groundwork for engineered biosynthesis of new bioactive polyketides.

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