Tuning the lipophilicity of new ciprofloxacin derivatives in selected ESKAPE bacteria with emphasis on E. coli mutants.

The objective of the present study was to improve the antimicrobial profile of ciprofloxacin by introducing a peptidomimetic function. A ciprofloxacin C3 carboxyl group was modified by a three-component Passerini reaction conducted under micellar conditions. The series of newly synthesized peptidomimetics was evaluated for their possible in vitro antibacterial activity toward including selected LPS-varied E. coli strains. A preliminary exploration of ciprofloxacin-based peptidomimetic analogues as novel antimicrobial agents was carried out to determine the basic characteristics of the structure responsible for the observed biological activity. The collected data demonstrated that an appropriate modification of the C3 position of ciprofloxacin significantly extends and improves antimicrobial activity, particularly against LPS-varied E. coli strains, which may cause various diseases such as urinary tract infections (UTI), enteric / diarrheal disease, and sepsis/meningitis. Furthermore, the antimicrobial activities of peptidomimetics against selected Gram-positive and Gram-negative bacterial strains belonging to ESKAPE bacteria (A. baumannii, P. aeruginosa, E. cloacae, and S. aureus) were investigated. All synthesized ciprofloxacin derivatives were found to be more potent antibacterial agents than the native compound. Most importantly, the introduction of a short aliphatic substituent into the peptidomimetic structure allowed to enhance and extend the activity of modified ciprofloxacin not only to the native E. coli strain but also to all of its tested mutants. The results showed that all tested peptidomimetics have enhanced antimicrobial activities (MIC values from 0.22 to 2.19 μM) as compared to ciprofloxacin (MIC = 0.62 to 3.44 μg/mL). Furthermore, the cytotoxicity of sixteen derivatives was measured using the MTT test on BALB/c3T3 mouse fibroblast cell lines. Cytotoxicity studies revealed that the tested substances exert a similar or lower effect on cell proliferation than that observed for native ciprofloxacin. This study presents that it is possible to extend the antimicrobial activity of ciprofloxacin by appropriate modification of its structure, which can prolong its use. This is very important in light of the reports incoming on pathogens in nosocomial infections that acquire resistance to this antibiotic.