Antibacterial activity and mechanism of action of a novel anilinouracil-fluoroquinolone hybrid compound.

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Butler MM, Lamarr WA, Foster KA, Barnes MH, Skow DJ, Lyden PT, Kustigian LM, Zhi C, Brown NC, Wright GE, Bowlin TL

Antibacterial activity and mechanism of action of a novel anilinouracil-fluoroquinolone hybrid compound.

Antimicrob Agents Chemother. 2007 Jan;51(1):119-27. Epub 2006 Oct 30.

PubMed ID

17074800 [ View in PubMed

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Abstract

The anilinouracils (AUs) such as 6-(3-ethyl-4-methylanilino)uracil (EMAU) are a novel class of gram-positive, selective, bactericidal antibacterials which inhibit pol IIIC, the gram-positive-specific replicative DNA polymerase. We have linked various fluoroquinolones (FQs) to the N-3 position of EMAU to generate a variety of AU-FQ "hybrids" offering the potential for targeting two distinct steps in DNA replication. In this study, the properties of a hybrid, "251D," were compared with those of representative AUs and FQs in a variety of in vitro assays, including pol IIIC and topoisomerase/gyrase enzyme assays, antibacterial, bactericidal, and mammalian cytotoxicity assays. Compound 251D potently inhibited pol IIIC and topoisomerase/gyrase, displayed gram-positive antibacterial potency at least 15 times that of the corresponding AU compound, and as expected, acted selectively on bacterial DNA synthesis. Compound 251D was active against a broad panel of antibiotic-resistant gram-positive pathogens as well as several gram-negative organisms and was also active against both AU- and FQ-resistant gram-positive organisms, demonstrating its capacity for attacking both of its potential targets in the bacterium. 251D also was bactericidal for gram-positive organisms and lacked toxicity in vitro. Although we obtained strains of Staphylococcus aureus resistant to the individual parent compounds, spontaneous resistance to 251D was not observed. We obtained 251D resistance in multiple-passage experiments, but resistance developed at a pace comparable to those for the parent compounds. This class of AU-FQ hybrids provides a promising new pharmacophore with an unusual dual mechanism of action and potent activity against antibiotic-sensitive and -resistant gram-positive pathogens.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Ciprofloxacin	DNA gyrase subunit A	Protein	Bacillus subtilis (strain 168)	Unknown	Not Available	Details
Ciprofloxacin	DNA topoisomerase 4 subunit B	Protein	Bacillus subtilis (strain 168)	Unknown	Not Available	Details