Antimicrobial activity of β-lactam antibiotics against clinical pathogens after molecular inclusion in several cyclodextrins. A novel approach to bacterial resistance

Abstract

Recognition and uptake by specific cellular receptors and transport systems for cyclodextrins have been demonstrated. Based on this concept, natural and synthetically modified cyclodextrins were used as drug carriers. Several beta-lactam antibiotics were selected and their inclusion complexes with different cyclodextrins were prepared (molar ratio ranging from 1:1 to 1:3). The complex formation, in aqueous solution, was monitored and optimum complexation conditions were selected. The inclusion of the active molecules in the cyclodextrin cavity was confirmed by (1)H NMR spectroscopy. Specific HPLC methods for the quantitation of antibiotics in the presence of cyclodextrins were developed and their chemical stability under complexation conditions was confirmed. Antimicrobial activity of drug-cyclodextrin complexes, in terms of minimum inhibitory concentration (MIC), were compared with the corresponding values of uncomplexed free molecules. A wide range of clinical pathogens and known beta-lactamase-producing strains were tested. The activity of the cyclodextrin-included antibiotics was increased, particularly against Gram-negative clinical strains. The nature and degree of substitution on cyclodextrin macromolecules may be the predominant factor in the observed improvement in antimicrobial activity. We believe that the proposed methodology is a novel approach to the microbial resistance problem and will trigger research towards the development of new cyclodextrin derivatives bearing the ability to increase the uptake of included antimicrobial molecules through intensification of the corresponding molecular recognition phenomena.

Antibacterial Activity of β-Cyclodextrin and 2-Hydroxypropyl-β-Cyclodextrin Trimethoprim Complexes

“…The nature and degree of substitution on CD macromolecules were proposed to be the predominant factors influencing the antimicrobial activity. (Athanassiou et al, 2003) Two mechanisms for these observed effects were suggested that may have relevance to our investigation. Firstly, several outermembrane bacterial proteins similar to CymA may have facilitated the penetration of the CD-drug complexes (Pajatsch et al, 1998;1999;Orlik et al, 2003).…”

“…Cyclodextrin (CD) complexation has been shown to alter the activity of several β-lactam antibiotics against a diverse panel of clinical isolates (Athanassiou et al, 2003). The antibacterial activities of these CDincluded antibiotics were shown to increase, particularly against Gram-negative bacteria.…”

“…CymA is an identified component of the outer membrane of Klebsiella oxytoca that functions as a porin specific for CD (Orlik et al, 2003). Secondly, CD molecules may have potentially destabilized the outer membrane of the bacteria, which eventually lead to an increase in the diffusion rate of the β-lactam antibiotics (Athanassiou et al, 2003).…”

Cyclodextrins: A Weapon in the Fight Against Antimicrobial Resistance

“…15 The antibacterial activity of CD-included antibiotics was increased relative to antibiotic controls. Inclusion complex of -CD and meropenem, for example, demonstrated greater growth inhibition and stability than the uncomplexed drug.…”

The Impact of Protein Binding on Antibacterial Activities of Antibiotics is more than Predicted by Considering its Numerical Value Alone: Effects of Serum Proteins on Activities of Poorly Penetrating Agents and Inhibition of ß- Lactamase Activity-Part II

“…Any decrease in the ability or rate of entry and an increased export, respectively, of these compounds can lead to resistance [23,24]. In theory, augmented intracellular accumulation [31,32] and/or efflux pump inhibition could restore the susceptibility of bacteria to antibiotics; however, efflux pump inhibitors have not yet progressed into clinical use [33,34]. Furthermore, human serum interacted synergistically with ß-lactams against ß-lactamase producing Gramnegative bacteria only but not against ß-lactamase negative strains due to ß-lactamase inhibition [11,12,35].…”