Development Of Resistance Research Articles

Computational Insight into the Mechanism of Action of DNA Gyrase Inhibitors; Revealing a New Mechanism.

Discovery of novel antimicrobial agents is in need to deal with antibiotic resistance. Elucidating the mechanism of action for established drugs contributes to this endeavor. DNA gyrase is a therapeutic target used in the design and development of new antibacterial agents. Selective antibacterial gyrase inhibitors are available; however, resistance development against them is a big challenge. Hence, novel gyrase inhibitors with novel mechanisms are required. In this study, the mechanism of action for selected DNA gyrase inhibitors available was carried out through molecular docking and molecular dynamics (MD) simulation. In addition, pharmacophore analysis, density functional theory (DFT) calculations, and computational pharmacokinetics analysis of the gyrase inhibitors were performed. This study demonstrated that all the DNA gyrase inhibitors investigated, except compound 14, exhibit their activity by inhibiting gyrase B at a binding pocket. The interaction of the inhibitors at Lys103 was found to be essential for the binding. The molecular docking and MD simulation results revealed that compound 14 could act by inhibiting gyrase A. A pharmacophore model that consisted of the features that would help the inhibition effect was generated. The DFT analysis demonstrated 14 had relatively high chemical stability. Computational pharmacokinetics analysis revealed that most of the explored inhibitors were estimated to have good drug-like properties. Furthermore, most of the inhibitors were found to be non-mutagenic. In this study, mode of action elucidation through molecular docking and MD simulation, pharmacophore model generation, pharmacokinetic property prediction, and DFT study for selected DNA gyrase inhibitors were carried out. The outcomes of this study are anticipated to contribute to the design of novel gyrase inhibitors.

Knowledge and perception of cereal farmers and extension agents on fungicide use in northern Ghana.

Agricultural pesticide use in sub-Saharan Africa has doubled over the past three decades, with a greater relative increase for fungicides. As pesticide inputs continue to rise, so does the potential for the development of resistance. Here, we report on a survey conducted to understand pesticide resistance awareness, pesticide-use knowledge and practices of growers and agricultural extension officers (AEOs) in the cereals growing-belt of northern Ghana, with emphasis on fungicides. The results may inform development of strategies for improving pesticide literacy including resistance awareness, extension services and crop protection outcomes. The survey revealed a low level of pesticide-use knowledge for AEOs and growers. This was more so for growers with low education, predominantly women. Education level (and indirectly gender) influenced perceived effectiveness of fungicides and levels of adoption of cultural and agrochemical best practices. Only 28% of growers and 11% of AEOs practiced crop and fungicide rotations, respectively. More than half (53%) of the respondents indicated that fungicides used in northern Ghana are not effective. Given the low level of pesticide literacy of AEOs and growers, training programs on best practice for the use of pesticides, with targeted initiatives for female growers, would improve crop protection outcomes and safety. The limited adoptions of crop rotation and repeated use of fungicides with the same active ingredients, along with >50% of respondents reporting 'fungicides not working' suggest the potential presence of fungicide resistance cases in growers' fields in the Northern region of Ghana. Further work is needed to determine the incidence of resistance in the region. It is recommended that a key policy priority should focus on understanding broader agrochemical-use practices, crop losses and household-level food security in the presence of resistance risks. © 2024 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

A Mathematical Analysis of Competitive Dynamics and Aggressive Treatment in the Evolution of Drug Resistance in Malaria Parasites

Experimental evidence supports the counterintuitive notion that rapid eradication of pathogens within a host, infected with both drug-sensitive and -resistant malaria parasites, can actually accelerate the evolution of drug-resistant pathogens. This study aims to analyze the competitive dynamics between these two strains through a mathematical model and evaluate the impact of aggressive treatment on the spread of drug resistance. We conducted equilibrium, uncertainty, and sensitivity analyses to assess the model, identifying and measuring the influence of key factors on the outcome variable (the population of drug-resistant parasites). Both equilibrium and local sensitivity analyses concurred that the density of drug-resistant parasites is notably affected by genetic instability, the production rate of red blood cells, the number of merozoites, and competition factors. Conversely, there is a negative relationship between genetic instability and one of the competition coefficients. Global sensitivity analysis offers a comprehensive examination of the impact of each input parameter on the temporal propagation of drug resistance, effectively accounting for the interplay among parameters. Both local and global sensitivity analyses underscore the continuous impact of drug treatment on the progression of drug resistance over time. This paper anticipates exploring the underlying mechanisms of drug resistance and providing theoretical support for developing more effective drug treatment strategies.

Piceatannol: a renaissance in antibacterial innovation unveiling synergistic potency and virulence disruption against serious pathogens.

In the relentless battle against multi-drug resistant Gram-negative bacteria, piceatannol emerges as a beacon of hope, showcasing unparalleled antibacterial efficacy and a unique ability to disrupt virulence factors. Our study illuminates the multifaceted prowess of piceatannol against prominent pathogens-Proteus mirabilis, Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. Notably, piceatannol demonstrated a remarkable ability to inhibit biofilm formation, reduce bacterial mobility, and diminish extracellular enzyme synthesis.Mechanistic insights into piceatannol's activity unraveled its impact on membrane potential, proton motive force, and ATP production. Furthermore, our study delved into piceatannol's anti-quorum sensing (QS) activity, showcasing its potential to downregulate QS-encoding genes and affirming its affinity to critical QS receptors through molecular docking. Crucially, piceatannol exhibited a low propensity for resistance development, positioning it as a promising candidate for combating antibiotic-resistant strains. Its mild effect on red blood cells (RBCs) suggests safety even at higher concentrations, reinforcing its potential translational value. In an in vivo setting, piceatannol demonstrated protective capabilities, significantly reducing pathogenesis in mice infected with P. aeruginosa and P. mirabilis. This comprehensive analysis positions piceatannol as a renaissance in antibacterial innovation, offering a versatile and effective strategy to confront the evolving challenges posed by resilient Gram-negative pathogens.

Interfacial thermal resistance between mechanically exfoliated nm-thick MoS2 and silicon from −60 °C to 50 °C based on ns-ET Raman technique

In the miniaturization and integration development of micro-devices, the large thermal contact resistance significantly affects the overall performance of micro-devices, which is influenced by both interfacial contact condition and material properties. However, the temperature dependence of interfacial thermal resistance of realistic materials remains unclear. In this work, the interfacial thermal resistance between nm-thick MoS2 nanosheets and Si substrate is measured by using the ns energy transport state-resolved Raman (ns ET-Raman) technique. By comparing the experimental data with finite difference numerical simulation, the real value of the interfacial thermal resistance is determined. By changing the ambient temperature from -60 °C to 50 °C, the interfacial thermal resistance against temperature curve is obtained. As the environmental temperature deviates from room temperature, a large increasement of the interfacial thermal resistance can be observed. As temperature goes back to room temperature, the unreversible interfacial thermal resistance indicates that the large thermal expansion mismatch deteriorates the contact situation. In the last, the interfacial thermal resistance evolution under varying environmental temperatures from both experiments and modeling results in literatures are compared and discussed to illustrate the effect of different interface formation methods. For epitaxial and CVD grown materials, the interfacial thermal resistance generally reduces with raising ambient temperature. While for mechanically exfoliated samples, the effect of thermal expansion mismatch and the resulting gaps dominate the interfacial thermal resistance, which leads to non-monotonous temperature dependency with a valley located at room temperature.

Preparation and Effects of Manganese Oxide Nanoparticles Against Quinolone-Resistant Bacteria Isolated from Hospital Wastewater

Background: The widespread administration of quinolones may have led to an increase in bacterial resistance development. Objective: To synthesize and characterize manganese oxide nanoparticles (MnO2NPs) and evaluate their effects on the viability and biofilm formation of quinolone-resistant gram-positive and negative pathogenic bacteria. Methods: We prepared MnO2NPs using the photo-irradiation method and recorded their characteristics using XRD, TEM, and SEM. Staphylococcus aureus, Streptococcus pneumonia, Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa were collected from the wastewater of Baghdad hospitals during the period from July 3rd to July 14th, 2023. We used the VITEK2 system to confirm and identify all of the isolates. We conducted biofilm formation and antibiotic susceptibility tests using nalidixic acid, ciprofloxacin, norfloxacin, aztreonam, levofloxacin, and ofloxacin, and also detected the qnrA and qnrB genes. Finally, we evaluated the effects of the prepared nanoparticles on the viability and biofilm formation of bacterial isolates. Results: MnO2NPs characterizations showed a diffraction peak at 2θ values with 21 nm average sizes; qnrA and qnrB genes were found in three and four isolates, respectively; and significant effects of MnO2NPs against viability and biofilm formation were recorded. Conclusions: The synthesized nanoparticles have antibacterial and anti-biofilm activities against a variety of bacteria possessing qnr genes. Even multi-resistant bacterial isolates have the potential to be strong antimicrobial agents against these pathogens.

Integrated analysis reveals critical cisplatin-resistance regulators E2F7 contributed to tumor progression and metastasis in lung adenocarcinoma

BackgroundDrug resistance poses a significant challenge in cancer treatment, particularly as a leading cause of therapy failure. Cisplatin, the primary drug for lung adenocarcinoma (LUAD) chemotherapy, shows effective treatment outcomes. However, the development of resistance against cisplatin is a major obstacle. Therefore, identifying genes resistant to cisplatin and adopting personalized treatment could significantly improve patient outcomes.MethodsBy examining transcriptome data of cisplatin-resistant LUAD cells from the GEO database, 181 genes associated with cisplatin resistance were identified. Using univariate regression analysis, random forest and multivariate regression analyses, two prognostic genes, E2F7 and FAM83A, were identified. This study developed a prognostic model utilizing E2F7 and FAM83A as key indicators. The Cell Counting Kit 8 assay, Transwell assay, and flow cytometry were used to detect the effects of E2F7 on the proliferation, migration, invasiveness and apoptosis of A549/PC9 cells. Western blotting was used to determine the effect of E2F7 on AKT/mTOR signaling pathway.ResultsThis study has pinpointed two crucial genes associated with cisplatin resistance, E2F7 and FAM83A, and developed a comprehensive model to assist in the diagnosis, prognosis, and evaluation of relapse risk in LUAD. Analysis revealed that patients at higher risk, according to these genetic markers, had elevated levels of immune checkpoints (PD-L1 and PD-L2). The prognostic and diagnosis values of E2F7 and FAM83A were further confirmed in clinical data. Furthermore, inhibiting E2F7 in lung cancer cells markedly reduced their proliferation, migration, invasion, and increased apoptosis. In vivo experiments corroborated these findings, showing reduced tumor growth and lung metastasis upon E2F7 suppression in lung cancer models.ConclusionOur study affirms the prognostic value of a model based on two DEGs, offering a reliable method for predicting the success of tumor immunotherapy in patients with LUAD. The diagnostic and predictive model based on these genes demonstrates excellent performance. In vitro, reducing E2F7 levels shows antitumor effects by blocking LUAD growth and progression. Further investigation into the molecular mechanisms has highlighted E2F7’s effect on the AKT/mTOR signaling pathway, underscoring its therapeutic potential. In the era of personalized medicine, this DEG-based model promises to guide clinical practice.

Therapy-induced APOBEC3A drives evolution of resistance to targeted therapies in non-small cell lung cancer

Therapy-induced APOBEC3A drives evolution of resistance to targeted therapies in non-small cell lung cancer

External quality assessment schemes in bacteriology support public health in Germany—results from 2006 to 2023

External Quality Assessment schemes (EQAS) are mandatory to ensure quality standards in diagnostic methods and achieve laboratory accreditation. As host institution for two German culture-based bacteriology EQAS (RV-A and RV-B), we investigated the obtained data of 590 up to 720 surveys per year in RV-A and 2,151 up to 2,929 in RV-B from 2006 to 2023. As educational instruments, they function to review applied methodology and are valuable to check for systemic- or method-dependent failures in microbiology diagnostics or guidelines. Especially, containment of multi-resistant bacteria in times of rising antibiotic resistance is one major point to assure public health. The correct identification and reporting of these strains is therefore of high importance to achieve this goal. Moreover, correct antimicrobial susceptibility testing (AST) per se is important for selecting appropriate therapy, to restrict broad-spectrum antibiotics and minimize resistance development. The reports of participating laboratories displayed a high level of correct identification results in both schemes with mostly consistent failure rates around 2.2% (RV-A) and 3.9% (RV-B) on average. In contrast, results in AST revealed increasing failure rates upon modification of AST requirements concerning adherence to standards and subsequent bacterial species-specific evaluation. Stratification on these periods revealed in RV-A a moderate increase from 1.3% to 4.5%, while in RV-B failure rates reached 14% coming from 4.3% on average. Although not mandatory, subsequent AST evaluation and consistent reporting are areas of improvement to benefit public health.

Bone marrow stromal cells induce chromatin remodeling in multiple myeloma cells leading to transcriptional changes.

The natural history of multiple myeloma is characterized by its localization to the bone marrow and its interaction with bone marrow stromal cells. The bone marrow stromal cells provide growth and survival signals, thereby promoting the development of drug resistance. Here, we show that the interaction between bone marrow stromal cells and myeloma cells (using human cell lines) induces chromatin remodeling of cis-regulatory elements and is associated with changes in the expression of genes involved in the cell migration and cytokine signaling. The expression of genes involved in these stromal interactions are observed in extramedullary disease in patients with myeloma and provides the rationale for survival of myeloma cells outside of the bone marrow microenvironment. Expression of these stromal interaction genes is also observed in a subset of patients with newly diagnosed myeloma and are akin to the transcriptional program of extramedullary disease. The presence of such adverse stromal interactions in newly diagnosed myeloma is associated with accelerated disease dissemination, predicts the early development of therapeutic resistance, and is of independent prognostic significance. These stromal cell induced transcriptomic and epigenomic changes both predict long-term outcomes and identify therapeutic targets in the tumor microenvironment for the development of novel therapeutic approaches.

Toxoplasma replication is inhibited by MMV676477 without development of resistance.

Protozoan parasites cause life-threatening infections in both humans and animals, including agriculturally significant livestock. Available treatments are typically narrow spectrum and are complicated by drug toxicity and the development of resistant parasites. Protozoan tubulin is an attractive target for the development of broad-spectrum antimitotic agents. The Medicines for Malaria Pathogen Box compound MMV676477 was previously shown to inhibit replication of kinetoplastid parasites, such as Leishmania amazonensis and Trypanosoma brucei, and the apicomplexan parasite Plasmodium falciparum by selectively stabilizing protozoan microtubules. In this report, we show that MMV676477 inhibits intracellular growth of the human apicomplexan pathogen Toxoplasma gondii with an EC50 value of ~50 nM. MMV676477 does not stabilize vertebrate microtubules or cause other toxic effects in human fibroblasts. The availability of tools for genetic studies makes Toxoplasma a useful model for studies of the cytoskeleton. We conducted a forward genetics screen for MMV676477 resistance, anticipating that missense mutations would delineate the binding site on protozoan tubulin. Unfortunately, we were unable to use genetics to dissect target interactions because no resistant parasites emerged. This outcome suggests that future drugs based on the MMV676477 scaffold would be less likely to be undermined by the emergence of drug resistance.

The LexA-RecA* structure reveals a cryptic lock-and-key mechanism for SOS activation.

The bacterial SOS response plays a key role in adaptation to DNA damage, including genomic stress caused by antibiotics. SOS induction begins when activated RecA*, an oligomeric nucleoprotein filament that forms on single-stranded DNA, binds to and stimulates autoproteolysis of the repressor LexA. Here, we present the structure of the complete Escherichia coli SOS signal complex, constituting full-length LexA bound to RecA*. We uncover an extensive interface unexpectedly including the LexA DNA-binding domain, providing a new molecular rationale for ordered SOS gene induction. We further find that the interface involves three RecA subunits, with a single residue in the central engaged subunit acting as a molecular key, inserting into an allosteric binding pocket to induce LexA cleavage. Given the pro-mutagenic nature of SOS activation, our structural and mechanistic insights provide a foundation for developing new therapeutics to slow the evolution of antibiotic resistance.

RICTOR/mTORC2 downregulation in BRAFV600E melanoma cells promotes resistance to BRAF/MEK inhibition.

The main drawback of BRAF/MEK inhibitors (BRAF/MEKi)-based targeted therapy in the management of BRAF-mutated cutaneous metastatic melanoma (MM) is the development of therapeutic resistance. We aimed to assess in this context the role of mTORC2, a signaling complex defined by the presence of the essential RICTOR subunit, regarded as an oncogenic driver in several tumor types, including MM. After analyzing The Cancer Genome Atlas MM patients' database to explore both overall survival and molecular signatures as a function of intra-tumor RICTOR levels, we investigated the effects of RICTOR downregulation in BRAFV600E MM cell lines on their response to BRAF/MEKi. We performed proteomic screening to identify proteins modulated by changes in RICTOR expression, and Seahorse analysis to evaluate the effects of RICTOR depletion on mitochondrial respiration. The combination of BRAFi with drugs targeting proteins and processes emerged in the proteomic screening was carried out on RICTOR-deficient cells in vitro and in a xenograft setting in vivo. Low RICTOR levels in BRAF-mutated MM correlate with a worse clinical outcome. Gene Set Enrichment Analysis of low-RICTOR tumors display gene signatures suggestive of activation of the mitochondrial Electron Transport Chain (ETC) energy production. RICTOR-deficient BRAFV600E cells are intrinsically tolerant to BRAF/MEKi and anticipate the onset of resistance to BRAFi upon prolonged drug exposure. Moreover, in drug-naïve cells we observed a decline in RICTOR expression shortly after BRAFi exposure. In RICTOR-depleted cells, both mitochondrial respiration and expression of nicotinamide phosphoribosyltransferase (NAMPT) are enhanced, and their pharmacological inhibition restores sensitivity to BRAFi. Our work unveils an unforeseen tumor-suppressing role for mTORC2 in the early adaptation phase of BRAFV600E melanoma cells to targeted therapy and identifies the NAMPT-ETC axis as a potential therapeutic vulnerability of low RICTOR tumors. Importantly, our findings indicate that the evaluation of intra-tumor RICTOR levels has a prognostic value in metastatic melanoma and may help to guide therapeutic strategies in a personalized manner.

Bioinformatics Approaches in the Development of Antifungal Therapeutics and Vaccines

Abstract: Fungal infections are considered a great threat to human life and are associated with high mortality and morbidity, especially in immunocompromised individuals. Fungal pathogens employ various defense mechanisms to evade the host immune system, which causes severe infections. The available repertoire of drugs for the treatment of fungal infections includes azoles, allylamines, polyenes, echinocandins, and antimetabolites. However, the development of multidrug and pandrug resistance to available antimycotic drugs increases the need to develop better treatment approaches. In this new era of -omics, bioinformatics has expanded options for treating fungal infections. This review emphasizes how bioinformatics complements the emerging strategies, including advancements in drug delivery systems, combination therapies, drug repurposing, epitope- based vaccine design, RNA-based therapeutics, and the role of gut-microbiome interactions to combat anti-fungal resistance. In particular, we focused on computational methods that can be useful to obtain potent hits, and that too in a short period.

SAFETY OF TETRACYCLINES FOR PUBLIC HEALTH AND THE ENVIRONMENT

Antimicrobial veterinary medicinal products of the tetracycline class have been most widely used for many years in the veterinary practice, both in Ukraine and in European countries, the USA, Canada, etc. Teteracyclynes have a wide-spectrum activity against gram-positive and gram-negative microorganisms, rickettsia, mycoplasma, chlamydia and protozoan parasites and are successfully used for the treatment of infectious diseases of the gastrointestinal tract, respiratory organs, skin and urogenital infections. Antimicrobial veterinary medicinal products of this class belong to AMEG category D, which is the safest in terms of impact on public health. Tetracyclines are low cost agents, are not high toxic when used in animals, which justifies their frequent choice for empirical treatment. During the monitoring of sales volumes for 2016-2021, antimicrobial veterinary medicinal products of the tetracycline class occupied the largest share among all antimicrobials entering the market in Ukraine (25.9-39.4)%. Most frequently, these veterinary medicinal products are intended for oral administration, but since their low bioavailability (5-15)%, they are excreted from the body almost unchanged. However, there is a danger of the development of tetracyclines resistance and a hazard to the environment and public health, which is explained by the frequent use of this class substances, the permission of large amounts into the soil with manure and water following drinkers washing after the treatment. Tetracyclines are poorly metabolized, and their long-term use in veterinary practice contributes to the bioaccumulation of significant amounts in soil and water. The main goal of this study were the analysis of veterinary medicinal products containing tetracyclines which were authorized in Ukraine by the category of active substances and route of administration. Another problem of this article was to substantiate the impact of tetracycline class antibiotics on the environment and the acquired antimicrobial resistance in the view of the necessity of their reasonable and safety use for the animals treatment, taking into account the requirements of the current legislation in Ukraine and EU member states. The results of the study proved that antimicrobial veterinary medicinal products containing chlortetracycline, mainly for oral administration, prevail in Ukraine. The bias of this monitoring is the lack information on the volumes of their use in farms and for individual animal species. Although the tetracycline class antibiotics do not belong to persistent bio accumulative toxic substances (PBT), their long-term and widespread use causes concern in view of the possible acquiring antimicrobial resistance and harmful effects on the environment, which will have an impact on public health. It is necessary to introduce regulatory measures to limitation and optimal use of these compounds in veterinary medicine. It is also necessary to deliver information among stakeholders about the possible negative impact on the environment and plan activities to prevent the development of acquired antimicrobial resistance to the tetracycline class antibiotics.

A predictive algorithm for the analysis of AMR trends and healthcare decision support

Background Translating available AMR surveillance data to observe evolving patterns of microbial resistance to antimicrobial agents while identifying regions at high risk of resistant cases and serving as a decision-support tool is an aspect of AMR surveillance that is rarely explored nationwide and uncommon globally. Therefore, we developed a two-tier dashboard algorithm (PATHFINDER) that can analyse antimicrobial surveillance datasets, observe evolving global spatiotemporal patterns of AMR, and integrate local AMR gene resources to identify functional AMR determinant genes and antibiotic classes from the query organism genome. Methods The Python-based plotly library was used to develop the interactive variables of the Antimicrobial Testing Leadership Surveillance (ATLAS) dataset in an adjustable spatiotemporal environment. A lightweight database containing multiple known resistant genes from the ResFinder database was used as a prototype to identify unique AMR determinant genes from query nucleotide sequences. In R, a function was created to accept query genome sequences and generate Kmers of length 250 using the blaster package. The GPT-4 API plug-in was embedded with adequate prompt parsing for it as an interpretation LLM function. Results AMR trendline plots were designed for invasive infections and customised based on the class of antibiotics and infection types on the surveillance dashboard. The decision-support tool correctly predicted resistant genes with a sensitivity of 75% on pre-confirmed organisms. The observed specificity score (51.5%) was due to the need for more filtering and optimisation and not to PATHFINDER performance. When run against the reference gene dataset containing pre-identified AMR genes, the support tool generated a BLAST table with identified AMR gene determinants in a nucleotide sequence. Conclusions The PATHFINDER algorithm has the potential to revolutionise healthcare decision-making. It can inform targeted interventions, guide antimicrobial stewardship efforts at a national level, promote appropriate antibiotic use, and significantly reduce the risk of resistance development.

Eminent Antimicrobial Peptide Resistance in Zymomonas mobilis: A Novel Advantage of Intrinsically Uncoupled Energetics

Relative to several model bacteria, the ethanologenic bacterium Zymomonas mobilis is shown here to have elevated resistance to exogenous antimicrobial peptides (AMPs)—with regard to both peptide bulk concentration in the medium and the numbers of peptide molecules per cell. By monitoring the integration of AMPs in the bacterial cell membrane and observing the resulting effect on membrane energy coupling, it is concluded that the membranotropic effects of the tested AMPs in Z. mobilis and in Escherichia coli are comparable. The advantage of Z. mobilis over E. coli apparently results from its uncoupled mode of energy metabolism that, in contrast to E. coli, does not rely on oxidative phosphorylation, and hence, is less vulnerable to the disruption of its energy-coupling membrane by AMPs. It is concluded that the high resistance to antimicrobial peptides (AMPs) observed in Z. mobilis not only proves crucial for its survival in its natural environment but also offers a promising platform for AMP production and sheds light on potential strategies for novel resistance development in clinical settings.

Using phage to drive selections toward restoring antibiotic sensitivity in Pseudomonas aeruginosa via chromosomal deletions

Phage therapy has re-emerged in modern medicine as a robust antimicrobial strategy in response to the increasing prevalence of antimicrobial-resistant bacteria. However, bacterial resistance to phages can also arise via a variety of molecular mechanisms. In fact, several clinical studies on phage therapy have reported the occurrence of phage-resistant variants, representing a significant concern for the successful development of phage-based therapies. In this context, the fitness trade-offs between phage and antibiotic resistance have revealed new avenues in the field of phage therapy as a countermeasure against phage resistance. This strategy forces to restore the antibiotic susceptibility of antimicrobial-resistant bacteria as compensation for the development of phage resistance. Here, we present the key achievements of these fitness trade-offs, notably focusing on the enhancement of antibiotic sensitivity through the induction of large chromosomal deletions by bacteriophage infection. We also describe the challenges of this strategy that need to be overcome to promote favorable therapeutic outcomes and discuss future directions. The insights gained from the trade-offs between phage and antibiotic sensitivity will help maximize the potential of phage therapy for the treatment of infectious diseases.

Essential oils as promising treatments for treating Candida albicans infections: research progress, mechanisms, and clinical applications

Candida albicans: (C. albicans) is a prevalent opportunistic pathogen that can cause severe mucosal and systemic fungal infections, leading to high morbidity and mortality rates. Traditional chemical drug treatments for C. albicans infection have limitations, including the potential for the development of drug resistance. Essential oils, which are secondary metabolites extracted from plants, have gained significant attention due to their antibacterial activity and intestinal regulatory effects. It makes them an ideal focus for eco-friendly antifungal research. This review was aimed to comprehensively evaluate the research progress, mechanisms, and clinical application prospects of essential oils in treating C. albicans infections through their antibacterial and intestinal regulatory effects. We delve into how essential oils exert antibacterial effects against C. albicans infections through these effects and provide a comprehensive analysis of related experimental studies and clinical trials. Additionally, we offer insights into the future application prospects of essential oils in antifungal therapy, aiming to provide new ideas and methods for the development of safer and more effective antifungal drugs. Through a systematic literature review and data analysis, we hope to provide insights supporting the application of essential oils in antifungal therapy while also contributing to the research and development of natural medicines. In the face of increasingly severe fungal infections, essential oils might emerge as a potent method in our arsenal, aiding in the effective protection of human and animal health.

Bioselective and Radiopaque Zinc-Biopolymeric Complex-Based Porous Biomaterials Promote Mammalian Tissue Ingrowth In Vivo While Inhibiting Microbial Biofilm Gene Expression and Biofilm Formation.

Metal-organic complexes have shown astounding bioactive properties; however, they are rarely explored as biomaterials. Recent studies showed that carboxymethyl-chitosan (CMC) genipin-conjugated zinc biomimetic scaffolds have unique bioselective properties. The biomaterial was reported to be mammalian cell-friendly; at the same time, it was found to discourage microbial biofilm formation on its surface, which seemed to be a promising solution to addressing the problem of trauma-associated biofilm formation and development of antimicrobial resistance. However, the mechanically frail characteristics and zinc overload raise concerns and limit the potential of the said biomaterials. Hence, the present work is focused on improving the strength of the earlier scaffold formulations, testing its in vivo efficacy and reaffirming its action against biofilm-forming microbe Staphylococcus aureus. Scaling up of CMC proportion increased rigidity, and 8% CMC was found to be the ideal concentration for robust scaffold fabrication. Freeze-dried CMC scaffolds with or without genipin (GP) cross-linking were conjugated with zinc using 2 M zinc acetate solution. Characterization results indicated that the CMC-Zn scaffolds, without genipin, showed mechanical properties close to bone fillers, resist in vitro enzymatic degradation until 4 weeks, are porous in nature, and have radiopacity close to mandibular bones. Upon implantation in a subcutaneous pocket of Wistar rats, the scaffolds showed tissue in-growth with simultaneous degradation without any signs of toxicity past 28 days. Neither were there any signs of toxicity in any of the vital organs. Considering many superior properties among the other formulations, the CMC-Zn scaffolds were furthered for biofilm studies. CMC-Zn showed negligible S. aureus biofilm formation on its surface as revealed by an alamar blue-based study. RT-PCR analysis revealed that CMC-Zn downregulated the expression of pro-biofilm effector genes such as icaC and clfB. A protein docking study predicted the inhibitory mechanism of CMC-Zn. Although it binds strongly when alone, at high density, it may cause inactivation of the transmembrane upstream activators of the said genes, thereby preventing their dimerization and subsequent inactivation of the effector genes. In conclusion, zinc-conjugated carboxymethyl-chitosan scaffolds are mechanically robust, porous, yet biodegradable, harmless to the host in the long term, they are radiopaque and prevent biofilm gene expression in notorious microbes; hence, they could be a suitable candidate for bone filler applications.