Mechanisms of emerging resistance associated with non-antibiotic antimicrobial agents: a state-of-the-art review.

Although the development of resistance by microorganisms to antimicrobial drugs has been recognized as a global public health concern, the contribution of various non-antibiotic antimicrobial agents to the development of antimicrobial resistance (AMR) remains largely neglected. The present review discusses various chemical substances and factors other than typical antibiotics, such as preservatives, disinfectants, biocides, heavy metals and improper chemical sterilization that contribute to the development of AMR. Furthermore, it encompasses the mechanisms like co-resistance and co-selection, horizontal gene transfer, changes in the composition and permeability of cell membrane, efflux pumps, transposons, biofilm formation and enzymatic degradation of antimicrobial chemicals which underlie the development of resistance to various non-antibiotic antimicrobial agents. In addition, the review addresses the resistance-associated changes that develops in microorganisms due to these agents, which ultimately contribute to the development of resistance to antibiotics. In order to prevent the indiscriminate use of chemical substances and create novel therapeutic agents to halt resistance development, a more holistic scientific approach might provide diversified views on crucial factors contributing to the persistence and spread of AMR. The review illustrates the common and less explored mechanisms contributing directly or indirectly to the development of AMR by non-antimicrobial agents that are commonly used.

Critical Strategies for Drug Precipitation Inhibition: A Review with the Focus on Poorly Soluble Drugs.

An oral route for drug administration is a more suitable route because of its ease of administration, pain avoidance, patient compliance, accommodation of various types of drug molecules, etc. But there are many factors affecting the oral absorption of the drugs. The main factor associated with oral absorption is drug solubility. Many new chemical molecules are poorly soluble in nature and can be included in BCS classes II and IV. For the administration of these drugs through the oral route, it was found that solubility is the rate limiting step. The low solubility of these drugs tends to cause precipitation in the gastrointestinaltract (GIT), affecting their bioavailability. Drug precipitation may be triggered by many factors such as insolubility of the drug in co-solvent, drug-excipient interactions, physiochemical properties of the drug, sudden change in the pH of the environment, incompatibility with the surfactant, etc. Precipitation of a drug may occur in two stages, formation of nucleation and crystal growth. To overcome precipitation, there are many strategies such as the use of polymers, the addition of surfactants, modulating drug loading and solubilizing capacity, change in the pH of the environment, etc. In this review, the causes of precipitation and diverse strategies of precipitation inhibition are critically reviewed.

Use of In silico tools for screening buffers to overcome physical instability of Abatacept.

Rheumatoid arthritis is an autoimmune disorder. Abatacept (CTLA4-Ig) is used for the treatment of Rheumatoid arthritis. Abatacept is a monoclonal antibody. Monoclonal antibodies undergo chemical (e.g. oxidation, deamidation, hydrolysis) and physical (e.g. aggregation, unfolding) instabilities while handling and storage. Abatacept is also prone to aggregation. Stabilizing agents such as buffers are used to stabilize monoclonal antibodies. But, the selection of the appropriate buffer is a time-consuming process because after testing many buffers based on the analysis of the results the appropriate buffer is identified. To overcome this issue in the current study computational tools were utilized to virtually screen different buffers to select the appropriate buffer. Ligand binding is the principal mechanism of conformational stability of proteins. For the buffers as well ligand binding is the most common mechanism for enhancing the thermodynamic stability of proteins. Generally it is observed that by enhancing the thermodynamic stability there is reduction in the rate of aggregation of proteins. Buffer (ligand) binds to the native state of the protein preferentially; it results in stabilization of the protein, while in the case of denatured protein it has no impact. There are many studies conducted involving the proteins in buffer solutions but very limited information is available about the mechanism of protein-buffer interactions. In the current study ligand binding mechanism of protein - buffer interaction was studied using molecular docking. After the docking buffers were ranked according to their energy value. The lower energy scores represent better protein-buffer (ligand) binding affinity compared to high energy values. It was observed that Phosphate with a binding affinity of -107.9 kcal/mol was the buffer with the least binding energy followed by Citrate (-70.6 kcal/mol), Melglumine (-66.6 kcal/mol), Arginine (-64.5 kcal/mol), Glucono delta lactone (-62.6 kcal/mol), Sodium citrate (-56.5 kcal/mol), Tromethamine (-52.3 kcal/mol), Glycine HCl (-37.2 kcal/mol), Sulfuric acid (-37.7 kcal/mol), Ammonium acetate (-31.1 kcal/mol), Acetic acid (-30.7 kcal/mol). With lower binding energy higher is the affinity between the ligand and protein. So phosphate was identified as a buffer with the highest affinity with Abatacept.

Copper-lowering agents as an adjuvant in chemotherapy.

Copper is an important element essential for metabolism and normal human body function. Although it is an essential element, related imbalance leads to toxic effects. Studies have proved that there is an increase in copper level in cancer cells. Evidences suggest the link between increase in copper levels and progression of various types of cancers. Different strategies have been utilized to decrease the level of copper in various types of cancer cells. However, it was observed that cell machinery involved in copper homeostasis plays critical factor in lowering copper levels in cancer cells. The outcomes of many monotherapies consisting copper-lowering agents for the treatment of different types of cancers showed that the inhibition of single factor is not sufficient to inhibit the growth of cancer cells. The combination of copper-lowering agent with chemotherapeutic agent showed synergistic effect. Interestingly, the presence of copper-lowering agent in such combinations significantly improved the efficacy of chemotherapeutic agent. The present work has focused on the discussion of outcomes of studies involving anti-copper agent and chemotherapeutic agent and related future strategies.

Potentiation of Antidepressant Effects of Agomelatine and Bupropion by Hesperidin in Mice.

Hesperidin, a well-known flavanone glycoside mostly found in citrus fruits, showed neuroprotective and antidepressant activity. Agomelatine, a melatonergic MT1/MT2 agonist and 5-HT2C receptor antagonist, exhibits good antidepressant efficacy. Bupropion has been widely used for the treatment of depression because of its dopamine and norepinephrine reuptake inhibition. The objective of present study was to assess the antidepressant effects of hesperidin combination with agomelatine or bupropion. Male Swiss Albino mice received treatment of saline, vehicle, 'hesperidin alone', 'agomelatine alone', hesperidin+agomelatine, 'bupropion alone', hesperidin+bupropion, and agomelatine+bupropion for 14 days. The immobility period was analysed 30 min after the treatment in forced swim and tail suspension tests. Dopamine and serotonin levels were analysed in hippocampus, cerebral cortex, and whole brain using HPLC with fluorescence detector. Hesperidin plus agomelatine treated group was better in terms of decrease in immobility period and increase in dopamine and serotonin levels when compared to their respective monotherapy treated groups.