Antibacterial activity of novel dual bacterial DNA type II topoisomerase inhibitors.

In this study, a drug discovery programme that sought to identify novel dual bacterial topoisomerase II inhibitors (NBTIs) led to the selection of six optimized compounds. In enzymatic assays, the molecules showed equivalent dual-targeting activity against the DNA gyrase and topoisomerase IV enzymes of Staphylococcus aureus and Escherichia coli. Consistently, the compounds demonstrated potent activity in susceptibility tests against various Gram-positive and Gram-negative reference species, including ciprofloxacin-resistant strains. The activity of the compounds against clinical multidrug-resistant isolates of S. aureus, Clostridium difficile, Acinetobacter baumannii, Neisseria gonorrhoeae, E. coli and vancomycin-resistant Enterococcus spp. was also confirmed. Two compounds (1 and 2) were tested in time-kill and post-antibiotic effect (PAE) assays. Compound 1 was bactericidal against all tested reference strains and showed higher activity than ciprofloxacin, and compound 2 showed a prolonged PAE, even against the ciprofloxacin-resistant S. aureus BAA-1720 strain. Spontaneous development of resistance to both compounds was selected for in S. aureus at frequencies comparable to those obtained for quinolones and other NBTIs. S. aureus BAA-1720 mutants resistant to compounds 1 and 2 had single point mutations in gyrA or gyrB outside of the quinolone resistance-determining region (QRDR), confirming the distinct site of action of these NBTIs compared to that of quinolones. Overall, the very good antibacterial activity of the compounds and their optimizable in vitro safety and physicochemical profile may have relevant implications for the development of new broad-spectrum antibiotics.
Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests: NDA, ACJ, GaM, RO, MV, CB, GM, CM, FPDG and ST are employees of Angelini S.p.A. LDS reports a grant in the context of the EUREKA project co-funded by Angelini S.p.A. and by Regione Marche, Universita Politecnica delle Marche (UNIVPM - Decreti Rettorali no. 740 July 2013 and no. 812 September 2013). The authors would like to declare the following patents/patent applications associated with this research: ACJ, GaM, RO and GM are inventors in patent WO2017/211759Al pending. This does not alter our adherence to PLOS ONE policies on sharing data and materials.