Trojan Antibiotics: New Weapons for Fighting Against Drug Resistance

Abstract

Bacterial resistance has caused a global healthcare emergency due to the buildup of antibiotics in the environment. Novel approaches that enable highly efficient bactericide and auto inactivation are highly desired. Past researches mainly focused on the on−off bactericidal ability of antibiotics, which often displays unsatisfactory bactericidal efficiency. Herein, we report a Trojan antibiotic that considers the affinity of antibiotics to bacteria. A disguised host−guest supramolecule based on cucurbituril (CB [7]) and a bola-type azobenzene compound with glycosylamine heads at both ends is synthesized. This supramolecule has a surface fully decorated with sugar-like components, which are highly analogous to wall components of bacteria. This Trojan antibiotic is benign to a wide spectrum of bacteria at a weak basic pH of approximately 9.0 under daylight conditions. However, this antibiotic becomes a potent bactericide toward both Gram-negative and Gram-positive bacteria at pH 4.0 under 365 nm UV irradiation. The dual use of pH and UV light greatly enhances the efficiency of the bactericidal effect so that the 50% minimum inhibitory concentration (MIC 50 ) of the Trojan antibiotic is at least 10 times smaller than that of conventional drugs, and the removal of the UV source and reversal of pH automatically stop the antibacterial behavior, which prevents the buildup of active antimicrobial materials in the environment. We expect that the presented Trojan supramolecular strategy may open up a new paradigm in the fight against bacterial resistance.

Applications of Cucurbiturils in Medicinal Chemistry and Chemical Biology

“…In a very recent report, a “Trojan antibiotic” has been formulated by a host-guest complex of CB7 and a bola-type azobenzene compound with glycosylamine heads at both ends (Wang et al, 2019). Similar to the bacterial wall, this supramolecular assembly displays a surface that is fully decorated with sugar-like components.…”

Cucurbit[7]uril Complexation of Near-Infrared Fluorescent Azobenzene-Cyanine Conjugates

“…One pragmatic way to enable the CB7 complexation of a heptamethine cyanine dye is to covalently append a CB7 binding unit to the cyanine dye such as adamantylamine, hexamethylenediamine, or ferrocene [ 10 , 14 , 15 , 16 ]. We were attracted to azobenzene as a relatively unexplored CB7 binding unit [ 17 , 18 , 19 , 20 , 21 ] and decided to investigate covalent azobenzene–cyanine conjugates. We reasoned that the conjugates might possess interesting hybrid properties that combine the NIR fluorescence of the cyanine component with the bioresponsiveness of the azobenzene component [ 22 , 23 , 24 , 25 , 26 ].…”

Azobenzene as Antimicrobial Molecules

“…Since the bacterial membrane is negatively charged, molecules with positively charged groups, such as quaternary ammonium salts, can interact with the bacterial membrane, so they are included in conventional antibacterial drugs [ 33 ].…”

“…Rapidly evolving bacteria species are capable of inhibiting the pharmacological action of molecules through several types of mechanisms, such as enzymatic inactivation, modification of drug targets, or biofilm formation. The low affinity of drugs for the bacterial cell wall requires high concentrations and long-term treatments to achieve the desired benefits and performance, resulting in the occurrence of serious adverse events [ 18 , 30 , 31 , 32 , 33 ]. Therefore, it is essential to research and develop new, efficient, and non-toxic alternatives to antimicrobial drugs using known, active substances.…”