Multi-targeted metallo-ciprofloxacin derivatives rationally designed and developed to overcome antimicrobial resistance

• Published in: International journal of antimicrobial agents 2021-12, Vol.58 (6), p.106449-106449, Article 106449
• Main Authors: Ude, Ziga, Flothkötter, Nils, Sheehan, Gerard, Brennan, Marian, Kavanagh, Kevin, Marmion, Celine J.
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Ciprofloxacin; Ciprofloxacin - analogs & derivatives; Ciprofloxacin - pharmacology; Copper; Copper - chemistry; Copper - pharmacology; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Multiple, Bacterial - genetics; Humans; Hydroxamic acid; Hydroxamic Acids - chemistry; Metallo-antibiotic; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - genetics; Moths - drug effects; Phenanthrenes - chemistry; Phenanthrenes - pharmacology; Proteomic analysis; Staphylococcal Infections - drug therapy; Staphylococcus aureus
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2021.106449

•A novel hydroxamate-based ciprofloxacin derivative was developed.•A new class of antibiotics, designed to overcome antimicrobial resistance, was developed.•Complexes possess potent antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus.•A detailed proteomic study on S. aureus exposed to ligand and complexes was conducted.•Proteins involved in virulence, pathogenesis and CAMP resistance pathway were affected. Antimicrobial resistance is a major global threat to human health due to the rise, spread and persistence of multi-drug-resistant bacteria or ‘superbugs’. There is an urgent need to develop novel chemotherapeutics to overcome this overarching challenge. The authors derivatized a clinically used fluoroquinolone antibiotic ciprofloxacin (Cip), and complexed it to a copper phenanthrene framework. This 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 represents a hydroxamic acid of Cip derivative. Comprehensive studies, including a detailed proteomic study in which Staphylococcus aureus cells were exposed to the complexes, were undertaken to gain an insight into their mode of action. These new complexes possess potent antibacterial activity against S. aureus and methicillin-resistant S. aureus. In addition, they were found to be well tolerated in vivo in Galleria mellonella larvae, which has both functional and structural similarities to the innate immune system of mammals. These 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 with clinically used Cip, including cationic antimicrobial peptide resistance. The Cu-DPPZ-CipHA (DPPZ = dipyrido[3,2-a:2’,3’-c]phenazine) analogue also induces cell leakage, which leads to an altered proteome indicative of reduced virulence and increased stress. [Display omitted] A new structural class of multi-targeted copper-ciprofloxacin antibiotics targeting antimicrobial resistance has been rationally designed and developed, and their mechanism of action has been investigated which included an extensive proteomic study.