Cheminformatics Analysis of Fluoroquinolones and their Inhibition Potency Against Four Pathogens

Drug-resistant bacteria are a worldwide public health concern. As the prevalence of multi-drug resistant pathogens outpaces the discovery of new antibacterials, it is of importance to explore the structure-activity relationships for series of known bactericides with proven scaffolds. Herein, we assembled a set of 507 fluoroquinolone analogues all experimentally tested for their inhibition potency against four pathogens: Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. We relied on cheminformatics techniques to characterize and cluster them based on their structural similarity and analyzed the structure-activity relationships identified for each cluster of fluoroquinolones. Then, we utilized machine learning techniques to develop and validate predictive QSAR models for computing the inhibition potencies (pMIC) of analogues for each pathogen. These QSAR models afforded reasonable external prediction performances (R2≥0.6, MAE∼0.4). This study confirmed that (i) there are both global and local inter-pathogen concordance regarding the antibacterial potency of fluoroquinolones, (ii) small clusters of fluoroquinolone analogues are characterized by unique patterns of strain selectivity and potency, the latter being potentially useful to design new analogues with enhanced potency and/or selectivity towards a given pathogen, and (iii) robust QSAR models were obtained allowing for future design of new bioactive fluoroquinolones.