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Antimicrobial Agents and Chemotherapy, October 2000, p. 2764-2770, Vol. 44, No. 10
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Prediction of Quinolone Activity against Mycobacterium avium by Molecular Topology and Virtual Computational Screening

Rafael Gozalbes,1,2 Monique Brun-Pascaud,3 Ramon García-Domenech,4 Jorge Gálvez,4 Pierre-Marie Girard,5 Jean-Pierre Doucet,2 and Francis Derouin1,*

Laboratoire de Parasitologie-Mycologie, Faculté de Médecine Lariboisière, Hôpital Saint-Louis, Université Paris 7, 75006 Paris,1 Institut de Topologie et de Dynamique des Systèmes (ITODYS), Université Paris 7, 75005 Paris,2 INSERM E9933, Hôpital Bichat, 75018 Paris,3 and Service des Maladies Infectieuses, Hôpital Rothschild, 75571 Paris Cedex 12,5 France, and Unidad de Investigación en Diseño de Fármacos y Conectividad Molecular, Departamento de Química-Física, Facultad de Farmacia, Universidad de Valencia, 46100 Burjassot, Spain4

Received 2 February 2000/Returned for modification 10 May 2000/Accepted 28 June 2000

We conducted a quantitative structure-activity relationship study using a database of 158 quinolones previously tested against Mycobacterium avium-M. intracellulare complex in order to develop a model capable of predicting the activity of new quinolones against the M. avium-M. intracellulare complex in vitro. Topological indices were used as structural descriptors and were related to anti-M. avium-M. intracellulare complex activity by using the linear discriminant analysis (LDA) statistical technique. The discriminant equation thus obtained correctly classified 137 of the 158 quinolones, including 37 of a test group of 44 randomly chosen compounds. This model was then applied to 24 quinolones, including recently developed fluoroquinolones, whose MICs were subsequently determined in vitro by using the Alamar blue microplate assay; the biological results confirmed the model's predictions. The MICs of these 24 quinolones were then treated by multilinear regression (MLR) to establish a model capable of classifying them according to their in vitro activities. Using this model, a good correlation between measured and predicted MICs was found (r2 = 0.88; r2cv [cross-validation correlation] = 0.82). Moxifloxacin, sparfloxacin, and gatifloxacin were the most potent against the M. avium- M. intracellulare complex, with MICs of 0.2, 0.4, and 0.9 µg/ml, respectively. Finally, virtual modifications of these three drugs were evaluated in LDA and MLR models in order to determine the importance of different substituents in their activity. We conclude that the combination of molecular-topology methods, LDA, and MLR provides an excellent tool for the design of new quinolone structures with enhanced activity.

* Corresponding author. Mailing address: Laboratoire de Parasitologie, Faculté de Médecine, 15 rue de l'Ecole de Médecine, 75006 Paris, France. Phone: 33 1 43 29 65 25. Fax: 33 1 43 29 51 92. E-mail: paracord{at}wanadoo.fr.

Antimicrobial Agents and Chemotherapy, October 2000, p. 2764-2770, Vol. 44, No. 10
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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