Each Antibiotics has its own Cyclodextrin (CD): Suitable, tailored, designed CD-derivatives for the encapsulation and revitalization of existing drugs

“Antimicrobial resistance (AMR) threatens the effective prevention and treatment of an ever-increasing range of infections caused by bacteria, parasites, viruses and fungi.” WHO is worried and warning about the current situation regarding the spread of resistant bacterial strains that severely disempower the effectiveness of currentantibiotics. The elaboration of methods to suppress resistance and repotentiate existing drugs is a much desired solution to this severe problem. Cyclodextrins (CDs)consist of 6, 7 or 8 α-1,4-linked D-glucopyranoseunits to form macrocyclicoligosaccharides (α-, β-or γ-CD, respectively) which are used as pharmaceutical excipients, thanks to their ability to enhance the water solubility and stability and bioavailability of hydrophobic drugs upon formation of supramolecular host : guest complexes. Multifunctional CD-based nanocarriers have been designed, synthesized and studied towards protection and repotentiation of antibiotics against resistant infections.ComprehensiveNMR and ITC studies were undertaken to screen the interaction of four β-lactam antibiotics with a panel of natural and specifically synthesized CDs,in order to investigate the effects of host size, flexibility and end-group charges on the binding with the drugs. Theresultsshowed that the engineered cysteamine-appended γ-CD (GCYS) forms the strongest inclusion complex with oxacillin (OXA, an antistaphylococcal penicillin) during an enthalpically and entropically favored process resulting in ΔGb= -18.5 kJ mol-1and Kb≈1700 M-1at 37 C. Moreover, GCYS protects OXA from hydrolysis by a specific oxa-1 β-lactamase enzyme produced by E. coli, reducing the corresponding rate by 2.3-fold. GCYSis also able to penetrate the cell walls of macrophages, enabling theeffective delivery ofOXA to mammalian cells.In another approach, a combination of NMR and UV-Vis spectroscopic investigationshighlighted the ability of heptakis(2,6-di-O-methyl)-βCD (DIMEB)to form complexes with rifampicin, an ansamycin antibiotic used as first-line treatment of tuberculosis. Enhanced water solubility and long-term stability of rifampicin was achieved upon complexation with DIMEBin neutral conditions via formation of a strong, 2: 1 complex (Kb1≈ 3000 M-1,Kb2≈10 M-1) at the piperazine site of the drug, accompanied bytwo more binding sites responsible for weaker bindings. Decreased host : guest affinity(Kb≈400 M-1)was observed at acidic pH (~4) dueto the completeprotonation of the piperazine moiety. Overall, the results suggestedthat DIMEBcould serve as a suitable delivery system conferring improved stability and pH-dependent release of the drug(e.g. in the stomach) for possible oral formulations.Then, we investigatedthe effectiveness of thepositively chargedGCYSto improve the delivery ofOXA and Rifampicinto bacterial biofilms. Using multiphoton laser scanning microscopy andsuper-resolutionfluorescence microscopy, we showed that fluorescein(FITC)-tagged GCYSis uniformly distributedthroughout live S. epidermidisbiofilm cultures in vitro,localized extracellularly. GCYS:Rifampicincomplex reduced100-foldthe biofilmviability compared torifampicin alone, plausibly because of theincreased solubility of rifampicin upon complexation and/or synergisticinterference with components of the biofilm.The results demonstrate that designed cyclodextrin nanocarriers efficiently deliver suitable antibiotics to biofilms and that fluorescence microscopy offers a novelapproach for mechanistic investigations