Unraveling resistance mechanisms in combination therapy: A comprehensive review of recent advances and future directions.

Antimicrobial resistance is a global health threat. Misuse and overuse of antimicrobials are the main drivers in developing drug-resistant bacteria. The emergence of the rapid global spread of multi-resistant bacteria requires urgent multisectoral action to generate novel treatment alternatives. Combination therapy offers the potential to exploit synergistic effects for enhanced antibacterial efficacy of drugs. Understanding the complex dynamics and kinetics of drug interactions in combination therapy is crucial. Therefore, this review outlines the current advances in antibiotic resistance's evolutionary and genetic dynamics in combination therapies-exposed bacteria. Moreover, we also discussed four pivotal future research areas to comprehend better the development of antibiotic resistance in bacteria treated with combination strategies.

Synthesis and Design of a Synthetic-Living Material Composed of Chitosan, Calendula officinalis Hydroalcoholic Extract, and Yeast with Applications as a Biocatalyst.

Design and development of materials that couple synthetic and living components allow taking advantage of the complexity of biological systems within a controlled environment. However, their design and fabrication represent a challenge for material scientists since it is necessary to synthesize synthetic materials with highly specialized biocompatible and physicochemical properties. The design of synthetic-living materials (vita materials) requires materials capable of hosting cell ingrowth and maintaining cell viability for extended periods. Vita materials offer various advantages, from simplifying product purification steps to controlling cell metabolic activity and improving the resistance of biological systems to external stress factors, translating into reducing bioprocess costs and diversifying their industrial applications. Here, chitosan sponges, functionalized with Calendula officinalis hydroalcoholic extract, were synthesized using the freeze-drying method; they showed small pore sizes (7.58 µm), high porosity (97.95%), high water absorption (1695%), and thermal stability, which allows the material to withstand sterilization conditions. The sponges allowed integration of 58.34% of viable Saccharomyces cerevisiae cells, and the cell viability was conserved 12 h post-process (57.14%) under storage conditions [refrigerating temperature (4 °C) and without a nutrient supply]. In addition, the synthesized vita materials conserved their biocatalytic activity after 7 days of the integration process, which was evaluated through glucose consumption and ethanol production. The results in this paper describe the synthesis of complex vita materials and demonstrate that biochemically modified chitosan sponges can be used as a platform material to host living and metabolically active yeast with diverse applications as biocatalysts.

Susceptibility for Some Infectious Diseases in Patients With Diabetes: The Key Role of Glycemia.

Uncontrolled diabetes results in several metabolic alterations including hyperglycemia. Indeed, several preclinical and clinical studies have suggested that this condition may induce susceptibility and the development of more aggressive infectious diseases, especially those caused by some bacteria (including Chlamydophila pneumoniae, Haemophilus influenzae, and Streptococcus pneumoniae, among others) and viruses [such as coronavirus 2 (CoV2), Influenza A virus, Hepatitis B, etc.]. Although the precise mechanisms that link glycemia to the exacerbated infections remain elusive, hyperglycemia is known to induce a wide array of changes in the immune system activity, including alterations in: (i) the microenvironment of immune cells (e.g., pH, blood viscosity and other biochemical parameters); (ii) the supply of energy to infectious bacteria; (iii) the inflammatory response; and (iv) oxidative stress as a result of bacterial proliferative metabolism. Consistent with this evidence, some bacterial infections are typical (and/or have a worse prognosis) in patients with hypercaloric diets and a stressful lifestyle (conditions that promote hyperglycemic episodes). On this basis, the present review is particularly focused on: (i) the role of diabetes in the development of some bacterial and viral infections by analyzing preclinical and clinical findings; (ii) discussing the possible mechanisms by which hyperglycemia may increase the susceptibility for developing infections; and (iii) further understanding the impact of hyperglycemia on the immune system.

Enhanced production of taxadiene in Saccharomyces cerevisiae.

BACKGROUND: Cost-effective production of the highly effective anti-cancer drug, paclitaxel (Taxol®), remains limited despite growing global demands. Low yields of the critical taxadiene precursor remains a key bottleneck in microbial production. In this study, the key challenge of poor taxadiene synthase (TASY) solubility in S. cerevisiae was revealed, and the strains were strategically engineered to relieve this bottleneck. RESULTS: Multi-copy chromosomal integration of TASY harbouring a selection of fusion solubility tags improved taxadiene titres 22-fold, up to 57 ± 3 mg/L at 30 °C at microscale, compared to expressing a single episomal copy of TASY. The scalability of the process was highlighted through achieving similar titres during scale up to 25 mL and 250 mL in shake flask and bioreactor cultivations, respectively at 20 and 30 °C. Maximum taxadiene titres of 129 ± 15 mg/L and 127 mg/L were achieved through shake flask and bioreactor cultivations, respectively, of the optimal strain at a reduced temperature of 20 °C. CONCLUSIONS: The results of this study highlight the benefit of employing a combination of molecular biology and bioprocess tools during synthetic pathway development, with which TASY activity was successfully improved by 6.5-fold compared to the highest literature titre in S. cerevisiae cell factories.

The Demand for New Antibiotics: Antimicrobial Peptides, Nanoparticles, and Combinatorial Therapies as Future Strategies in Antibacterial Agent Design.

The inappropriate use of antibiotics and an inadequate control of infections have led to the emergence of resistant strains which represent a major threat to public health and the global economy. Therefore, research and development of a new generation of antimicrobials to mitigate the spread of antibiotic resistance has become imperative. Current research and technology developments have promoted the improvement of antimicrobial agents that can selectively interact with a target site (e.g., a gene or a cellular process) or a specific pathogen. Antimicrobial peptides and metal nanoparticles exemplify a novel approach to treat infectious diseases. Nonetheless, combinatorial treatments have been recently considered as an excellent platform to design and develop the next generation of antibacterial agents. The combination of different drugs offers many advantages over their use as individual chemical moieties; these include a reduction in dosage of the individual drugs, fewer side effects compared to the monotherapy, reduced risk for the development of drug resistance, a better combined response compared to the effect of the individual drugs (synergistic effects), wide-spectrum antibacterial action, and the ability to attack simultaneously multiple target sites, in many occasions leading to an increased antibacterial effect. The selection of the appropriate combinatorial treatment is critical for the successful treatment of infections. Therefore, the design of combinatorial treatments provides a pathway to develop antimicrobial therapeutics with broad-spectrum antibacterial action, bactericidal instead of bacteriostatic mechanisms of action, and better efficacy against multidrug-resistant bacteria.

Metabolic Engineering and Synthetic Biology: Synergies, Future, and Challenges.

The "-omics" era has brought a new set of tools and methods that have created a significant impact on the development of Metabolic Engineering and Synthetic Biology. These fields, rather than working separately, depend on each other to prosper and achieve their individual goals. Synthetic Biology aims to design libraries of genetic components (promoters, coding sequences, terminators, transcriptional factors and their binding sequences, and more), the assembly of devices, genetic circuits and even organism; in addition to obtaining quantitative information for the creation of models that can predict the behavior of biological systems (Cameron et al., 2014). Metabolic engineering seeks for the optimization of cellular processes, endemic to a specific organism, to produce a compound of interest from a substrate, preferably cheap and simple. It uses different databases, libraries of components and conditions to generate the maximum production rate of a desired chemical compound and avoiding inhibitors and conditions that affect the growth rate and other vital functions in the specific organism to achieve these goals; metabolic fluxes manipulation represents an important alternative (Stephanopoulos, 2012).