Efficacies of ABT-719 and related 2-pyridones, members of a new class of antibacterial agents, against experimental bacterial infections

Alder, Jeff; Clement, Jacob J.; Meulbroek, Jonathan A.; Shipkowitz, N. L.; Mitten, Michael J.; Jarvis, Ken; Oleksijew, Anatol; Hutch, Thomas B.; Paige, L.; Flamm, Bernd

doi:10.1128/aac.39.4.971

Cited by 20 publications

(8 citation statements)

References 18 publications

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“…ABT-719 ( Fig. 1) is a 2-pyridone inhibitor of bacterial DNA gyrase differing from a fluoroquinolone by placement of the nitrogen atom in the ring juncture (19,20). Ten micrograms of ABT-719 added to a 6-mm blank disk produced an inhibitory zone of 13 mm on a lawn of E. coli J53 Azi r but a 6-mm (no inhibition) zone with J53 Azi r pMG252, indicating that qnrA1 protects against ABT-719.…”

Section: Resultsmentioning

confidence: 99%

Protective Effect of Qnr on Agents Other than Quinolones That Target DNA Gyrase

Jacoby

Corcoran

Hooper

2015

Antimicrob Agents Chemother

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bQnr is a plasmid-encoded and chromosomally determined protein that protects DNA gyrase and topoisomerase IV from inhibition by quinolones. Despite its prevalence worldwide and existence prior to the discovery of quinolones, its native function is not known. Other synthetic compounds and natural products also target bacterial topoisomerases. A number were studied as molecular probes to gain insight into how Qnr acts. Qnr blocked inhibition by synthetic compounds with somewhat quinolone-like structure that target the GyrA subunit, such as the 2-pyridone ABT-719, the quinazoline-2,4-dione PD 0305970, and the spiropyrimidinetrione pyrazinyl-alkynyl-tetrahydroquinoline (PAT), indicating that Qnr is not strictly quinolone specific, but Qnr did not protect against GyrA-targeting simocyclinone D8 despite evidence that both simocyclinone D8 and Qnr affect DNA binding to gyrase. Qnr did not affect the activity of tricyclic pyrimidoindole or pyrazolopyridones, synthetic inhibitors of the GyrB subunit, or nonsynthetic GyrB inhibitors, such as coumermycin A1, novobiocin, gyramide A, or microcin B17.Thus, in this set of compounds the protective activity of Qnr was confined to those that, like quinolones, trap gyrase on DNA in cleaved complexes. Qnr was discovered as a plasmid-encoded protein that reduces susceptibility to quinolones (1). Quinolones are synthetic compounds that target the essential bacterial enzymes DNA gyrase and topoisomerase IV, homologous tetramers composed of GyrA and GyrB or ParC and ParE subunits, respectively, that introduce negative supercoils or unknot and decatenate the DNA helix with energy from ATP hydrolysis (2).Qnr is a pentapeptide repeat protein that blocks quinolone inhibition of both topoisomerases and binds to each of their subunits as well as to the holoenzymes (3-5). Many bacteria have qnr-like genes on the chromosome, some, especially in aquatic bacteria, closely related to plasmid-determined qnr varieties (6-8). The native function of these proteins, which clearly antedate the clinical use of quinolones, is not known.A number of other agents target topoisomerases. Well-studied natural products include coumermycin A1 (9, 10), gyramide A (11), microcin B17 (12), novobiocin (9, 10), and simocyclinone D8 (13,14). From mutational and other studies the sites of action of many of these agents are known. For example, the primary site of resistance mutations for quinolones in Gram-negative bacteria is a region on the GyrA subunit known as the quinolone resistance-determining region (QRDR) (15), while novobiocin targets ATPase activity of the GyrB subunit (9). Qnr does not protect against novobiocin inhibition of gyrase (16), but the protective effect of Qnr on other natural products is not yet known. Medicinal chemists have synthesized synthetic compounds of various structures intended to act on gyrase at sites different from those directly affected by quinolones, especially the GyrB subunit. Whether Qnr protects gyrase from such compounds has not been investigated. The aim of this study was to...

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Section: Resultsmentioning

confidence: 99%

Protective Effect of Qnr on Agents Other than Quinolones That Target DNA Gyrase

Jacoby

Corcoran

Hooper

2015

Antimicrob Agents Chemother

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“…ABT-719 (28) was also referred to as A-86719.1 for the hydrochloride salt and as A-86719.0 for the free base. 109 The hydrochloride salts of ABT-719 and ABT-255 were found to be extremely soluble in water ( b 16 mg/mL) (Table XXXVII). ABT-719 and ABT-255 showed 3-to 83-fold and 38-to 1000-fold increases, respectively, in solubility at physiological pH as compared to tosu¯oxacin and cipro¯oxacin.…”

Section: E C H a N I S M O F A C T I O N O F 2 -P Y R I D O N E Smentioning

confidence: 99%

The 2-pyridone antibacterial agents: bacterial topoisomerase inhibitors

2000

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“…The efficacy of ABT-773 was compared to that of penicillin and/or clarithromycin in murine models of acute bacterial infections as described previously (3,12). In brief, CF1 female mice (Charles River, Wilmington, Mass.)…”

Section: Methodsmentioning

confidence: 99%

Efficacies of ABT-773, a New Ketolide, against Experimental Bacterial Infections

Mitten

Meulbroek

Nukkala

et al. 2001

Antimicrob Agents Chemother

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ABT-773 is a novel ketolide effective against antibacterial-resistant respiratory tract pathogens. The pharmacokinetic profile of ABT-773 was studied in rats and consisted of a mean peak concentration in plasma of 1.07 g/ml and an area under the concentration-time curve (AUC) of 12.03 g ⅐ h/ml when the compound was delivered at a dose of 25 mg/kg of body weight. It concentrated in rat lung tissue, with a lung tissue-to-plasma ratio of 29 based on the AUC. In acute systemic infections in mice, ABT-773 showed efficacy against macrolidesusceptible strains of Staphylococcus aureus, Streptococcus pneumoniae, S. pyogenes, and Listeria monocytogenes. Additionally, ABT-773 improved the survival of mice infected with resistant S. pneumoniae containing either the ermB gene, the mefE gene, or altered penicillin binding protein genes. In a rat lung model of infection, ABT-773 demonstrated 50% effective doses lower than those of comparator macrolides when evaluated against the following strains of S. pneumoniae: a macrolide-lincosamide-streptogramin B-susceptible strain, an ermB strain, and an mefE strain. ABT-773 was also effective against Haemophilus influenzae lung infections in rats. Thus, ABT-773 may prove to be a useful new antibacterial agent for the treatment of respiratory tract infections.

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Efficacies of ABT-719 and related 2-pyridones, members of a new class of antibacterial agents, against experimental bacterial infections

Cited by 20 publications

References 18 publications

Protective Effect of Qnr on Agents Other than Quinolones That Target DNA Gyrase

Protective Effect of Qnr on Agents Other than Quinolones That Target DNA Gyrase

The 2-pyridone antibacterial agents: bacterial topoisomerase inhibitors

Efficacies of ABT-773, a New Ketolide, against Experimental Bacterial Infections

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