The increasing prevalence of antimicrobial resistance is a global healthcare concern;1 evidence suggests that at least 700,000 people worldwide die every year due to antimicrobial resistance.2 Numerous studies have aimed to (i) decipher the resistance mechanisms of emerging drug resistant pathogens and (ii) devise innovative strategies to intercept the persistence of resistant bacterial strains.
Each bacterial cell contains a range of specialized enzymes called topoisomerases that play a crucial role in key cellular events such as DNA replication. Depending on their structure, homology and catalytic mechanisms, topoisomerases are classified into type I and type II, based on the type of DNA breaks introduced i.e., single-stranded and double-stranded breaks, respectively.3 The extensively researched type II topoisomerases are further subdivided (based on their structure and catalytic cycle features) into classes IIA and IIB, of which type IIA encompasses two key functional enzymes, namely DNA gyrase and topoisomerase IV.4 These specialized enzymes serve as attractive targets for an array of antibiotics, including fluoroquinolones (FQs), a well-known class of antibiotics.5 Evidence suggests that FQs target type II topoisomerases and their enzymes DNA gyrase and topoisomerase IV by stabilizing a covalent cleavage complex between the enzyme and the DNA with a double-stranded break that is toxic for a cell.6 Recently, there have been some reports of E. coli isolates that may be resistant to FQs, owing to mutations developing in the topoisomerase-encoding genes. To combat the potential for FQ resistance, the concept of ‘reverse antibiotics’ has been explored.5
Nybomycins (NYBs), an attractive class of compounds termed ‘reverse antibiotics’ have been found to selectively inhibit the growth some gram-positive FQR bacteria (e.g., S. aureus) by targeting the mutant form of DNA gyrase, while being inactive against wild-type strains with FQ-sensitive (FQS) gyrases.5 Meanwhile, the activity of NYBs against gram-negative species such as E. coli is less defined. A group of researchers from Russia explored the activity of NYBs on gram-negative isogenic FQR and FQS E. coli strains to elucidate their potential in combating antimicrobial resistance.5
Key findings of the study include:
In conclusion, Shiriaev and colleagues emphasized the promising ‘reverse antibiotic’ potential of NYBs in antibacterial chemotherapy focused at maintaining the therapeutic efficacy of FQs. Furthermore, the cytotoxic potency of NYBs observed may provide rationale for research on its potential utility in anticancer therapeutics.