Current scenario of quinolone hybrids with potential antibacterial activity against ESKAPE pathogens

The ESKAPE (Escherichia coli/E. coli, Staphylococcus aureus/S. aureus, Klebsiella pneumonia/K. pneumoniae, Acinetobacter Baumannii/A. baumannii, Pseudomonas aeroginosa/P. aeroginosa and Enterobacter spp.) pathogens, which could escape or evade common therapies through diverse antimicrobial resistance mechanisms and biofilm formation, are deemed as highly virulent bacteria responsible for life-threatening diseases, calling for novel chemotherapeutics. Quinolones including 2-quinolones and 4-quinolones have occupied a propitious place in drug design and development due to their excellent pharmacological profiles. Quinolones especially fluoroquinolones could inhibit the synthesis of nucleic acid of ESKAPE pathogens, leading to the rupture of bacterial chromosome. However, the resistance of ESKAPE pathogens to quinolones develops rapidly and spreads widely. Accordingly, it has become increasingly urgent to enhance the potency of quinolones against both drug-susceptible and drug-resistant ESKAPE pathogens. Quinolone hybrids can bind with different drug targets simultaneously and have been considered as useful prototypes to circumvent drug resistance. The purpose of this review is to summarize the current scenario (2018-present) of quinolone hybrids with potential antibacterial activity against ESKAPE pathogens, together with the structure-activity relationships and mechanisms of action to facilitate further rational design of more effective candidates.