Covalent Conjugates of Allylbenzenes and Terpenoids as Antibiotics Enhancers with the Function of Prolonged Action

Abstract

The drug resistance of pathogenic bacteria is often due efflux pumps—specific proteins that remove foreign compounds from bacterial cells. To overcome drug resistance, adjuvants are often used that can inhibit efflux pumps or other systems that ensure the resistance of bacteria to the action of antibiotics. We assumed that a new level of effectiveness with the use of an antibiotic + an adjuvant pair could be achieved by their joint delivery into the pathogen. To test this hypothesis, we constructed a series of molecular carriers based on poly-(olygo-, dendry)mers based on cyclodextrin-grafted PEI or mannan, as well as glycol chitosan, covalently bound to antibiotic, adjuvant, and the oligosaccharide ligand to the macrophage mannose receptor (CD206), which we studied earlier and showed high efficiency and selectivity of delivery of a therapeutic “cargo” to macrophages. Moxifloxacin was used as an antibiotic, and terpenoid and allylbenzene compounds were used as adjuvants, for which we previously discovered the ability to inhibit bacterial efflux pumps. We show that: (a) the resulting structures were stable in vitro for a long time (up to 10 days); (b) they were adsorbed on bacterial cells, providing a local increase in the concentration of the antibiotic and adjuvant in pathogen cells; (c) they were internalized by bacterial cells, ensuring the accumulation of both antibiotic and adjuvant inside bacterial cells; (d) the adjuvant, after entering the bacterial cell, provided inhibition of the efflux pumps; (e) due to this action of the adjuvant, combined with the targeted delivery by the carrier, the antibiotic’s half-life in rats increased by more than 2 times, the effective concentration of the drug in the blood plasma (AUC) increased up to 8–10 times; (f) a significant increase in the effectiveness of the antibacterial action against Gram+ and Gram- cells was achieved (up to 3 times). Potentially, such an approach would significantly increase the effectiveness of therapies for a number of infectious and other diseases, reduce the dosage of antibiotics, shorten the duration of treatment, and reduce the risk of developing bacterial resistance. Moreover, the use of a polymer carrier with covalently bound organic molecules of different structures will avoid problems linked to different (suboptimal) solubility and bio-distribution of the administered molecules, which would be almost inevitable when using the same compounds separately. It would be very difficult to find antibiotic/adjuvant pairs that simultaneously achieve optimal concentrations in the same target cells. In our case, terpenoids and alkylbenzenes used as adjuvants are practically insoluble as individual compounds, and their unacceptable pharmacological properties would not allow them to be used as efflux pump inhibitors.

Biomimetic Systems Involving Macrophages and Their Potential for Targeted Drug Delivery

“…The use of mannosylated drug delivery systems using the idea of biomimetics for oligosaccharidic patterns of microorganisms to target macrophage mannose receptors has been recently studied in detail by our scientific group in a series of papers [192,[276][277][278][279][280] (Figure 6), in which we aimed to create a targeted drug delivery system for the treatment of a number of infectious, inflammation and oncological diseases. On the basis of ligands specific to the macrophage receptor CD206, a system of targeted delivery of therapeutic "cargo", enhanced with adjuvants (showing a synergistic effect with the main drug), into macrophages was developed [192,278,[280][281][282][283][284][285][286][287] (Figure 6 shows a macrophage with its receptors recognizing mannosylated polymers). The use of a macrophage CD206 receptor as a target provides a high selectivity for drug delivery and does not require the use of immune-active compounds (interleukins, proteins, microRNAs, etc.).…”

“…A significant increase in efficiency can be achieved by using adjuvants, which enhance the effect of an antibiotic by inhibiting efflux and increasing the permeability of the bacterial membrane [280,284,285]. Currently, the direction of biocompatible medicine is actively developing, in other words, the use of safe natural extracts and essential oils [278,284,[289][290][291][292][293][294][295][296][297][298][299][300][301][302], which have a number of remarkable biological effects, including analgesic, antibacterial, anti-inflammatory, antitumor, antioxidant and regenerating properties.…”

Biomimetic System Based on Reconstituted Macrophage Membranes for Analyzing and Selection of Higher-Affinity Ligands Specific to Mannose Receptor to Develop the Macrophage-Focused Medicines

“…We considered 3 analytical applications of CD206 receptor-based biosensing. The first one is targeted delivery systems of the drugs to macrophages, which we considered in a series of our papers [22][23][24][33][34][35][36][37][38]. The development of the macrophage CD206 receptor-based biosensor would provide an effective testing system for optimizing of the structure of the specific ligands to alveolar macrophages for the therapy of the macrophageassociated diseases.…”

Triphenylphosphine Derivatives of Allylbenzenes Express Antitumor and Adjuvant Activity When Solubilized with Cyclodextrin-Based Formulations

“…In this regard, the non-toxic components of natural extracts and oils attract attention as potential adjuvants to strengthen the main drug (antibacterial or antitumor drug) and reduce the off-target effects. The individual components of essential oils (allylbenzenes [44][45][46][47], terpenoids [48,49], terpenes [50][51][52], flavonoids [30,53,54], Thai herbs [55], etc.) have antioxidant, antibacterial, restorative and antitumor properties, and, moreover, they are effective inhibitors of efflux pumps [3,5,6,9,[14][15][16][17]20,21,28,[56][57][58][59][60] that cause bacterial resistance to antibiotics and the resistance of cancer cells to cytostatics.…”

“…Apiol (1-allyl-2,5-dimethoxy-3,4-methylenedioxybenzene), a component of parsley oil, inhibits cytochrome P450 3A4 (IC 50 7.9 µM) [19,36,44,58,[77][78][79][80], which metabolizes xenobiotics in the liver, reducing their bioavailability. Apiol demonstrates weak antibacterial and anticancer activities, but at the same time, it dramatically enhances the effect of antibiotics (for example, moxi-or levofloxacin) [44,77] and cytostatics (doxorubicin, paclitaxel, etc.) [49] by inhibiting P-glycoprotein.…”