In vitro anti-Mycobacterium avium activities of quinolones: predicted active structures and mechanistic considerations

Abstract

The relationship between the structures of quinolones and their anti-Mycobacterium avium activities has been previously derived by using the Multiple Computer-Automated Structure Evaluation program. A number of substructural constraints required to overcome the resistance of most of the strains have been identified. Nineteen new quinolones which qualify under these substructural requirements were identified by the program and subsequently tested. The results show that the substructural attributes identified by the program produced a successful a priori prediction of the anti-M. avium activities of the new quinolones. All 19 quinolones were found to be active, and 4 of them are as active or better than ciprofloxacin. With these new quinolones, the updated multiple computer-automated structure evaluation program structure-activity relationship analysis has helped to uncover additional information about the nature of the substituents at the C5 and C7 positions needed for optimal inhibitory activity. A possible explanation of drug resistance based on the observation of suicide inactivation of bacterial cytochrome P-450 by the cyclopropylamine moiety has also been proposed and is discussed in this report. Furthermore, we confirm the view that the amount of the uncharged form present in a neutral pH solution plays a crucial role in the drug's penetration ability.Quinolones, more specifically, fluoroquinolones, have shown great potential in treating Mycobacterium avium-M intracellulare complex (MAI) infection, the most common bacterial infection complicating AIDS (6, 18). Although a large number of quinolone analogs have been made and their activities against some groups of bacteria, such as gram positive, gram negative, tuberculosis causing, etc., have been tested (36), only a limited number of quinolones have been tested for activity against MAI (25,42).To discover quinolones more potent against drug-resistant MAI organisms, we have previously tested 88 quinolones against a spectrum of M avium strains and identified relevant quantitative structure-activity relationships by Multiple Computer-Automated Structure Evaluation (MULTICASE) analysis (22, 23). From the activity spectrum of the 88 quinolones, we found variable and progressive resistance of the selected M avium strains. On the basis of susceptibility to quinolones, the strains used in our tests have been classified into a continuum between the most susceptible and the most resistant strains. In our previous analysis, we found that quinolones active against susceptible strains are not always active against resistant strains while those effective against resistant strains always exhibit good activities against susceptible strains. Furthermore, our previous studies have shown that as the susceptibility of the strains decreases, the identified substructures of quinolones required for the inhibitory activity become more restrictive. However, whether this progressive resistance is due to more selective penetration of the bacterial cell membrane or more restrictive bi...

Mycobacterium tuberculosis DNA Gyrase: Interaction with Quinolones and Correlation with Antimycobacterial Drug Activity

“…Analysis of the quinolone structureactivity relationship showed that these seven compounds shared certain structural features (C-8 with or lacking a substitution, N-1 cyclopropyl group, a ring at C-7, and a fluorine at C-6) (see Table 1). Quinolone structure-activity relationship analyses done to date for quinolones and mycobacteria (21,24,32,38) were not based on target inhibition, as in our study, but on MICs, which are the result of target inhibition and many other factors of activity, such as cell wall permeability and efflux (19). Moreover, these analyses were done with nontuberculous mycobacteria (M. smegmatis, M. avium, and M. fortuitum) and not with M. tuberculosis.…”

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

“…A database of 158 quinolones with known anti-M. avium-M. intracellulare complex activities has been built up from several articles by Klopman et al (20,21,23). Each quinolone was characterized by a set of 145 TIs specific to each molecule.…”

“…On the basis of the data of Klopman et al (20,21,23), the quinolones studied here were separated into active and inactive compounds according to their MICs around a cutoff of 32 g/ml. In accordance with the studies of Klopman et al, this cutoff was selected since it allowed a clear differentiation between active and inactive drugs.…”

“…The structure of each molecule is represented by specific subsets of topological indices (TIs). Klopman et al first developed computer-based predictive models to characterize anti-M. avium-M. intracellulare complex activity (20,21,23). The aim of this study was to develop new QSAR models, based on TIs, statistical linear discriminant analysis (LDA), and multilinear regression (MLR) in order to predict the in vitro activity and MICs of quinolones against the M. avium-M. intracellulare complex.…”

Comparison of activities of fluoroquinolones in murine macrophages infected with Mycobacterium tuberculosis

“…Wells were periodically observed under a microscope to check for cell viability or Fig. 1; synthesis and other characteristics of these compounds are described elsewhere (11,12).…”