Current Pharmaceutical Design - Volume 29, Issue 5, 2023

Antibiotics are commonly used to treat bacterial infections. For many years, antibiotics have been used at sub-therapeutic doses to promote animal growth and misused as prophylactics and metaphylactic on farms. The widespread and improper use of antibiotics has resulted in a serious problem, defined as antibiotic resistance by the World Health Organisation, which is a major public health threat in the 21st century. Bacteria have evolved sophisticated mechanistic strategies to avoid being killed by antibiotics. These strategies can be classified as intrinsic resistance (referring to the inherent structural or functional characteristics of a bacterial species) or acquired resistance (referring to mutations in chromosomal genes or the acquisition of external genetic determinants of resistance). In farm animals, the use of antibiotics warrants serious consideration, as their residues leach into the environment through effluents and come into contact with humans through food. Several factors have contributed to the emergence of antibiotic-resistant bacteria. This review provides an update on antibiotic resistance mechanisms, while focusing on the effects of this threat on veterinary medicine, and highlighting causal factors in clinical practice. Finally, it makes an excursus on alternative therapies, such as the use of bacteriophages, bacteriocins, antimicrobial photodynamic therapy, phytochemicals, and ozone therapy, which should be used to combat antibiotic-resistant infections. Some of these therapies, such as ozone therapy, are aimed at preventing the persistence of antibiotics in animal tissues and their contact with the final consumer of food of animal origin.

Antibiotic resistance can be characterized, in biochemical terms, as an antibiotic’s inability to reach its bacterial target at a concentration that was previously effective. Microbial resistance to different agents can be intrinsic or acquired. Intrinsic resistance occurs due to inherent functional or structural characteristics of the bacteria, such as antibiotic-inactivating enzymes, nonspecific efflux pumps, and permeability barriers. On the other hand, bacteria can acquire resistance mechanisms via horizontal gene transfer in mobile genetic elements such as plasmids. Acquired resistance mechanisms include another category of efflux pumps with more specific substrates, which are plasmid-encoded. Efflux pumps are considered one of the main mechanisms of bacterial resistance to antibiotics and biocides, presenting themselves as integral membrane transporters. They are essential in both bacterial physiology and defense and are responsible for exporting structurally diverse substrates, falling into the following main families: ATP-binding cassette (ABC), multidrug and toxic compound extrusion (MATE), major facilitator superfamily (MFS), small multidrug resistance (SMR) and resistance-nodulation-cell division (RND). The Efflux pumps NorA and Tet(K) of the MFS family, MepA of the MATE family, and MsrA of the ABC family are some examples of specific efflux pumps that act in the extrusion of antibiotics. In this review, we address bacterial efflux pump inhibitors (EPIs), including 1,8-naphthyridine sulfonamide derivatives, given the pre-existing knowledge about the chemical characteristics that favor their biological activity. The modification and emergence of resistance to new EPIs justify further research on this theme, aiming to develop efficient compounds for clinical use.

Use of antibiotics has dramatically eradicated bacterial infections in humans and animals. However, antibiotic overdose and abuse are responsible for the emergence of so-called multi-drug resistant bacteria. Gut microbiota deserves many functions in the host, and among them, integrity of epithelial barrier and enhancement of protective immune responses are included. There is evidence that antibiotic treatment decreases the diversity of gut microbiota species, also provoking metabolic changes, increased susceptibility to colonization and decrease of antimicrobial peptide secretion, leading to antibiotic resistance. In this review, the major mechanisms involved in antibiotic resistance will be illustrated. However, novel findings on the potential use of alternative treatments to overcome antibiotic resistance will be elucidated. In this regard, special emphasis will be placed on microcins, prebiotics, probiotics and postbiotics, as well as phage therapy and fecal microbial transplantation.

Background: Scutellarin exerts anticancer effects on diverse malignancies. However, its function in gastric cancer has not been explored. Objective: This study aimed to examine the anticancer effect and molecular mechanism of scutellarin in gastric cancer. Materials and Methods: Gastric cancer cells were treated with scutellarin and transfected with the Wnt1 overexpression plasmid. Cell viability, proliferation, toxicity, and apoptosis were determined by cell counting kit-8 (CCK-8), colony formation, lactate dehydrogenase (LDH) activity, TdT-mediated dUTP Nick-End Labeling (TUNEL), and flow cytometry assays. Expressions of apoptosis-related and Wnt/β-catenin signaling pathway- related proteins were examined by western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results: Scutellarin concentration dependently restrained cell viability. Scutellarin (20 and 80 μmol/L) suppressed proliferation and promoted LDH release and apoptosis. Moreover, scutellarin elevated Bax and Cytochrome C levels but diminished the levels of Bcl-2, Wnt1, cytoplasmic β-catenin, and basal cytoplasmic β- catenin. However, the above-mentioned regulatory effects of scutellarin were all reversed by Wnt1 overexpression. Conclusion: Scutellarin suppressed gastric cancer cell proliferation and promoted apoptosis by inhibition of the Wnt/β-catenin pathway.

Background: At present, there are no effective pharmacologic therapies for attenuating the course of osteoarthritis (OA) in humans and current therapies are geared to mitigating symptoms. Fangfeng decoction (FFD) is a traditional Chinese medicine prescribed for the treatment of OA. In the past, FFD has achieved positive clinical outcomes in alleviating the symptoms of OA in China. However, its mechanism of action has not yet been clarified. Objective: The objective of this study is to investigate and explore the mechanism of FFD and how the compound interacts with the target of OA; network pharmacology and molecular docking methods were applied in this study. Methods: The active components of FFD were screened by Traditional Chinese Medicine Systems Pharmacology (TCMSP) database according to the inclusion criteria as oral bioactivity (OB) ≥ 30% and drug likeness (DL) ≥ 0.18. Then, gene name conversion was performed through the UniProt website. The related target genes of OA were obtained from the Genecards database. Core components, targets, and signaling pathways were obtained through compound-target-pathway (C-T-P) and protein-protein interaction (PPI) networks were built using Cytoscape 3.8.2 software. Matescape database was utilized to get gene ontology (GO) function enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of gene targets. The interactions of key targets and components were analyzed by molecular docking in Sybyl 2.1 software. Results: A total of 166 potential effective components, 148 FFD-related targets, and 3786 OA-related targets were obtained. Finally, 89 common potential target genes were confirmed. Pathway enrichment results showed that HIF-1 and CAMP signaling pathways were considered key pathways. The screening of core components and targets was achieved through the CTP network. The core targets and active components were obtained according to the CTP network. The molecular docking results showed that quercetin, medicarpin, and wogonin of FFD could bind to NOS2, PTGS2, and AR, respectively. Conclusion: FFD is effective in the treatment of OA. It may be caused by the effective binding of the relevant active components of FFD to the targets of OA.