Comparative study of new benzenesulphonamide fluoroquinolones structurally related to ciprofloxacin against selected ciprofloxacin-susceptible and -resistant Gram-positive cocci

Q2 · MEDICINE

Article

Author: Nieto, M. ; Barnes, A. ; Alovero, F. ; Mazzieri, M. R. ; Manzo, R. H.

The in vitro activities of benzenesulphonamide fluoroquinolones (BSFQs) I-III, new fluoroquinolones with a p-substituted benzenesulphonyl moiety attached to the C(7) piperazinyl ring of ciprofloxacin, were assessed in comparison with those of N-sulfanilylpiperazinyl fluoroquinolone (NSFQ)-105 and ciprofloxacin for 133 Gram-positive clinical isolates. NSFQ-105 and BSFQ-I were the most active drugs. They were 16- to 64-fold more active than ciprofloxacin against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, including ciprofloxacin-resistant strains, and Streptococcus pneumoniae (eight- to 32-fold). A high degree of correlation was found between the MICs of the new compounds and ciprofloxacin for Staphylococcus spp. and E. faecalis. Staphylococci and enterococci exhibit cross-resistance to BSFQs and ciprofloxacin.

01 Feb 2000·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Engineering the Specificity of Antibacterial Fluoroquinolones: Benzenesulfonamide Modifications at C-7 of Ciprofloxacin Change Its Primary Target in Streptococcus pneumoniae from Topoisomerase IV to Gyrase

Q2 · MEDICINE

Article

Author: Alovero, Fabiana L. ; Manzo, Ruben H. ; Fisher, L. Mark ; Morris, Julia E. ; Pan, Xiao-Su

ABSTRACT We have examined the antipneumococcal mechanisms of a series of novel fluoroquinolones that are identical to ciprofloxacin except for the addition of a benzenesulfonylamido group to the C-7 piperazinyl ring. A number of these derivatives displayed enhanced activity against Streptococcus pneumoniae strain 7785, including compound NSFQ-105, bearing a 4-(4-aminophenylsulfonyl)-1-piperazinyl group at C-7, which exhibited an MIC of 0.06 to 0.125 μg/ml compared with a ciprofloxacin MIC of 1 μg/ml. Several complementary approaches established that unlike the case for ciprofloxacin (which targets topoisomerase IV), the increased potency of NSFQ-105 was associated with a target preference for gyrase: (i) parC mutants of strain 7785 that were resistant to ciprofloxacin remained susceptible to NSFQ-105, whereas by contrast, mutants bearing a quinolone resistance mutation in gyrA were four- to eightfold more resistant to NSFQ-105 (MIC of 0.5 μg/ml) but susceptible to ciprofloxacin; (ii) NSFQ-105 selected first-step gyrA mutants (MICs of 0.5 μg/ml) encoding Ser-81-to-Phe or -Tyr mutations, whereas ciprofloxacin selects parC mutants; and (iii) NSFQ-105 was at least eightfold more effective than ciprofloxacin at inhibiting DNA supercoiling by S. pneumoniae gyrase in vitro but was fourfold less active against topoisomerase IV. These data show unequivocally that the C-7 substituent determines not only the potency but also the target preference of fluoroquinolones. The importance of the C-7 substituent in drug-enzyme contacts demonstrated here supports one key postulate of the Shen model of quinolone action.

01 Jun 1998·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Mode of Action of Sulfanilyl Fluoroquinolones

Q2 · MEDICINE

Article

Author: Manzo, Ruben H. ; Nieto, Marcelo ; Mazzieri, Maria Rosa ; Then, Rudolf ; Alovero, Fabiana

ABSTRACT The mode of action of sulfanilyl fluoroquinolones (NSFQs) was investigated with NSFQ-104, NSFQ-105, and some structurally related compounds. Evidence arising from interactions with p -aminobenzoic acid and trimethoprim suggested that a sulfonamidelike mechanism of action makes little or no contribution to the in vitro activity of NSFQs. NSFQ-105 showed an activity that inhibits gyrase-catalyzed DNA supercoiling that is similar to the activity of other fluoroquinolones. Also, NSFQ-105 uptake was decreased by the presence of Mg 2+ and increased by a lower pH. These results indicate that NSFQs having only one ionizable group could exhibit more favorable kinetics of access to the bacterial cell than zwitterionic fluoroquinolones.

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Indication	Highest Phase	Country/Location	Organization	Date
Bacterial Infections	Discovery	US	Hoffmann-La Roche, Inc.	-

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