Multi-Targeted Metallo-Ciprofloxacin Derivatives Rationally Designed and Developed to Overcome Antimicrobial Resistance

Int J Antimicrob Agents. 2021 Oct 10:106449. doi: 10.1016/j.ijantimicag.2021.106449. Online ahead of print.

ABSTRACT

Antimicrobial resistance is a major global threat to human health due to the rise, spread and persistence of multidrug-resistant bacteria or 'superbugs'. There is an urgent need to develop novel chemotherapeutics to overcome this overarching challenge. We have derivatised a clinically used fluoroquinolone antibiotic ciprofloxacin and complexed it to a copper phenanthrene framework. This has resulted in the development of two novel metallo-antibiotics of general formula [Cu(N,N)(CipHA)]NO3 where N,N represents a phenanthrene ligand and CipHA stands for a hydroxamic acid of a ciprofloxacin (Cip) derivative. Comprehensive studies, including a detailed proteomic study in which S. aureus cells were exposed to the complexes, were undertaken to gain an insight into their mode of action. These new complexes possess potent anti-bacterial activity against Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA). In addition, they were found to be well tolerated in vivo in Galleria mellonella larvae, which has both functional and structural similarities to that of the innate immune system of mammals. Our findings suggest that proteins involved in virulence, pathogenesis and the synthesis of nucleotides and DNA repair mechanisms are most affected. In addition, both complexes affected similar cell pathways when compared to the clinically used Cip, including CAMP resistance. The Cu-DPPZ-CipHA (DPPZ = dipyrido[3,2-a:2',3'-c]phenazine) analogue also induces cell leakage, which leads to altered proteome indicative of reduced virulence and increased stress.

PMID:34644603 | DOI:10.1016/j.ijantimicag.2021.106449