Fluoroquinolones as versatile scaffolds: Potential for targeting classical and novel mechanisms to combat antibacterial resistance

Antibiotics play an essential role in combating infectious diseases. Due to the emergence of multidrug-resistant bacteria, the efficacy of antibiotic therapy is continually decreasing. Consequently, there is an urgent need for the development of novel antibiotics, preferably with novel targets that have not yet been clinically exploited and/or multiple mechanisms of action, reducing the probability of fast resistance development. Recently, several new promising antibacterial targets have been identified, including N-acetylglucosamine-6-phosphate deacetylase, glucosamine-6-phosphate synthase, metal-dependent deacetylase, and carbonic anhydrase. Additionally, inhibition of biofilm formation enhances bacterial susceptibility to antibiotics and potentially minimizes the risk of resistance development. This review discusses fluoroquinolones as versatile scaffolds, covering their structure-activity relationships, recent modifications and their role in inhibiting multiple bacterial targets. Multi-target fluoroquinolone derivatives exhibit enhanced activity against multidrug-resistant bacteria, including Gram-positive, Gram-negative, and mycobacterial species. Therefore, the continued optimization of fluoroquinolone structures represents an attractive approach to combat antibacterial resistance and achieve better therapeutic outcomes.