Enhancing antibacterial efficacy through macrocyclic host complexation of fluoroquinolone antibiotics for overcoming resistance

Abstract

The use of supramolecular assemblies in pharmaceuticals has garnered significant interest. Recent studies have shown that the activities of antibacterial agents can be enhanced through complexation with cyclic oligomers and metal ions. Notably, these complexes sometimes possess greater therapeutic properties than the parent drugs. To develop microbiologically potent supramolecular drugs, the complexation of macrocyclic hosts with fluoroquinolone (FQ) antibiotics was investigated. FQs are a successful family of antibiotics that target the bacterial enzymes DNA gyrase and DNA topoisomerase IV, leading to bacterial cell death through the inhibition of DNA synthesis. However, antibiotic resistance resulting from the repeated use of FQs over time has limited their effectiveness against resistant pathogens. To overcome this issue, the encapsulation of FQs in polyphenolic macrocycles was investigated. This study highlights resorcinarene, a polyphenolic host with antibacterial properties, and its ability to chemically interact with FQs. The inclusion complexation process was analyzed using NMR and FTIR techniques. The binding constants determined by ¹H-NMR titration revealed that levofloxacin forms more stable complexes with resorcinarene than with β-cyclodextrin, which aligned with MD simulations. Assessment of the geometric characteristics of the inclusion complexes using 2D NMR analysis confirmed that different moieties of various FQs can fit into a single host cavity and improve activity against gram-negative bacteria. Overall, these findings suggest that encapsulation in polyphenolic macrocycles is a promising strategy for utilizing FQs against antibiotic-resistant bacteria.

Keywords: Antibacterial efficacy; Antibiotic resistance; Antibiotics; Fluroquinolones; Macrocyclic host–guest complex; Resistant bacteria; Supramolecular interactions.

Fig. 1

Structures of hosts: (a) sulfonato-C-methylresorcin[4]arene (SRsC1), a synthetic cyclic polyphenol, and (b) β-cyclodextrin (β-CD); and fluoroquinolone (FQ) guest molecules: (c) levofloxacin (LEVO), (d) norfloxacin (NOR), and (e) ciprofloxacin (CIPRO).

Fig. 2

Nonlinear curve fitting for complexation between FQ guests (LEVO, CIPRO, and NOR) and macrocyclic hosts (β-CD and SRsC1) in D₂O (5% NaOD in D₂O for CIPRO and NOR) at 298 K. The experimental results are shown as filled symbols and the theoretical data are shown as solid lines.

Fig. 3

¹H–¹H NOE spectra of equimolar mixtures (0.05 M each) of (a) SRsC1–LEVO, (b) SRsC1–CIPRO, and (c) SRsC1–NOR in 5% NaOD in D₂O at 283.15 K. Interactions between two protons are represented by circles or ovals of the same color.

Fig. 4

FTIR spectra of individual components, an equimolar physical mixture (PM), and an equimolar freeze-dried (FD) complex for (a) SRsC1–LEVO, (b) β-CD–LEVO, (c) SRsC1–NOR, and (d) SRsC1–CIPRO.

Fig. 5

Distances between the COMhost and COMguest. The data for SRsC1–LEVO and β-CD–LEVO when LEVO is initially within SRsC1/β-CD and above SRsC1/β-CD are shown in (a) and (b), respectively. The data for SRsC1–CIPRO and SRsC1–NOR when CIPRO/NOR is initially within SRsC1 and above SRsC1 are shown in (c) and (d), respectively.

Fig. 6

Interactions of (a) SRsC1–LEVO and (b) SRsC1–CIPRO. Solvent is not shown for clarity.

Fig. 7

Effect of complexed FQ antibiotics against resistant (R) strains of P. aeruginosa: (a) CIPRO, SRsC1–CIPRO, (b) NOR, SRsC1–NOR, (c) LEVO, SRsC1–LEVO, and (d) LEVO, β-CD–LEVO. Values represent the mean ± SD (standard deviation). Student’s paired two-tailed t-test, * statistically significant value with p < 0.05 for macrocycle–FQ complexes vs. FQs (control).