Exploration of the Activity of 7-Pyrrolidino-8-methoxyisothiazoloquinolones against Methicillin-Resistant Staphylococcus aureus (MRSA)
2011; American Chemical Society; Volume: 54; Issue: 9 Linguagem: Inglês
10.1021/jm101604v
ISSN1520-4804
AutoresHa-Young Kim, Jason A. Wiles, Qiuping Wang, Godwin C. G. Pais, Edlaine Lucien, Akihiro Hashimoto, David M. Nelson, Jane A. Thanassi, Steven D. Podos, Milind Deshpande, Michael J. Pucci, Barton J. Bradbury,
Tópico(s)Antibiotic Resistance in Bacteria
ResumoA series of 7-(3'-substituted)pyrrolidino-8-methoxyisothiazoloquinolone (ITQ) analogues were prepared, and their antibacterial potency against methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), and Escherichia coli were compared. Many of these analogues had MIC ≤ 0.25 μg/mL against quinolone-resistant MRSA strains. The stereochemical preference was explored for a series of 1''-methyl-3'-aminomethylpyrrolidine analogues. Antibacterial activity was generally more favorable with 3'-R, 1''-S configuration. Substitution on the 3'-aminomethyl nitrogen tended to decrease activity, while potency was maintained with disubstitution or aryl substitution at the 1''-carbon. The 7-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl] analogue (6a(R,S)) and the (R)-7-[3-(2-aminopropan-2-yl)pyrrolidin-1-yl] analogue (7a(R)) were found to be the ITQs with the most promising antibacterial profiles. The MICs of these select ITQs versus a panel of clinical MRSA strains were determined, and the ITQs were found to have 8- to 16-fold greater potency than linezolid. These analogues were also evaluated for inhibition of the target enzymes, topoisomerase IV and DNA gyrase, from both wild-type and multidrug resistant strains. The ITQs were up to >30 times more inhibitory against these targets than the fluoroquinolone moxifloxacin.
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