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Cellular metabolism continuously processes an enormous range of external compounds into endogenous metabolites and is as such a key element in human physiology. The multifaceted physiological role of the metabolic network fulfilling the catalytic conversions can only be fully understood from a whole-body perspective where the causal interplay of the metabolic states of individual cells, the surrounding tissue and the whole organism are simultaneously considered. We here present an approach relying on dynamic flux balance analysis that allows the integration of metabolic networks at the cellular scale into standardized physiologically-based pharmacokinetic models at the whole-body level. To evaluate our approach we integrated a genome-scale network reconstruction of a human hepatocyte into the liver tissue of a physiologically-based pharmacokinetic model of a human adult. The resulting multiscale model was used to investigate hyperuricemia therapy, ammonia detoxification and paracetamol-induced toxication at a systems level. The specific models simultaneously integrate multiple layers of biological organization and offer mechanistic insights into pathology and medication. The approach presented may in future support a mechanistic understanding in diagnostics and drug development. [ABSTRACT FROM AUTHOR]

Non-communicable diseases (NCDs) represent a global health challenge, constituting a major cause of mortality and disease burden in the 21st century. Addressing the prevention and management of NCDs is crucial for improving global public health, emphasizing the need for comprehensive strategies, early interventions, and innovative therapeutic approaches to mitigate their far-reaching consequences. Marine organisms, mainly algae, produce diverse marine natural products with significant therapeutic potential. Harnessing the largely untapped potential of algae could revolutionize drug development and contribute to combating NCDs, marking a crucial step toward natural and targeted therapeutic approaches. This review examines bioactive extracts, compounds, and commercial products derived from macro- and microalgae, exploring their protective properties against oxidative stress, inflammation, cardiovascular, gastrointestinal, metabolic diseases, and cancer across in vitro, cell-based, in vivo, and clinical studies. Most research focuses on macroalgae, demonstrating antioxidant, anti-inflammatory, cardioprotective, gut health modulation, metabolic health promotion, and anti-cancer effects. Microalgae products also exhibit anti-inflammatory, cardioprotective, and anti-cancer properties. Although studies mainly investigated extracts and fractions, isolated compounds from algae have also been explored. Notably, polysaccharides, phlorotannins, carotenoids, and terpenes emerge as prominent compounds, collectively representing 42.4% of the investigated compounds. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance (AMR) poses a significant threat to the health, social, environment, and economic sectors on a global scale and requires serious attention to addressing this issue. Acinetobacter baumannii was given top priority among infectious bacteria because of its extensive resistance to nearly all antibiotic classes and treatment options. Carbapenem-resistant A. baumannii is classified as one of the critical-priority pathogens on the World Health Organization (WHO) priority list of antibiotic-resistant bacteria for effective drug development. Although available genetic manipulation approaches are successful in A. baumannii laboratory strains, they are limited when employed on newly acquired clinical strains since such strains have higher levels of AMR than those used to select them for genetic manipulation. Recently, the CRISPR-Cas (Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein) system has emerged as one of the most effective, efficient, and precise methods of genome editing and offers target-specific gene editing of AMR genes in a specific bacterial strain. CRISPR-based genome editing has been successfully applied in various bacterial strains to combat AMR; however, this strategy has not yet been extensively explored in A. baumannii. This review provides detailed insight into the progress, current scenario, and future potential of CRISPR-Cas usage for AMR-related gene manipulation in A. baumannii. [ABSTRACT FROM AUTHOR]

Alveolar echinococcosis (AE) is caused by the larval stage of Echinococcus multilocularis. Chemotherapy for AE involves albendazole (ABZ), which has shown insufficient efficacy. More effective chemotherapy for AE is needed. Previously, we have demonstrated that atovaquone (ATV), an antimalarial, inhibits mitochondrial complex III of E. multilocularis and restricts the development of larval cysts in in vivo experiments. Therefore, in this study, we evaluated the efficacy of ABZ and ATV combination therapy on E. multilocularis in culture and in vivo experiments. Protoscoleces were treated with 50 μM ABZ and/or ATV in the medium; the duration of parasite elimination was determined under aerobic and anaerobic culture. In the in vivo experiment, the effects of ABZ and ATV combination treatment in BALB/c mice infected orally with eggs from the feces of an adult-stage E. multilocularis-infected dog were compared with those of standard oral ABZ therapy. In the culture assay, the duration of elimination associated with ABZ and ATV combination treatment was shorter than that associated with ATV alone under aerobic conditions. Protoscolex viability progressively reduced owing to the combination treatment under anaerobic conditions; however, either drug used singly did not exhibit antiparasitic effects under hypoxia. Furthermore, compared with ABZ alone, the combination treatment significantly reduced the growth of the primary cyst in the liver of mice infected orally with parasite eggs (P =.011). ATV enhances the effect of ABZ in the treatment of AE in mice. [ABSTRACT FROM AUTHOR]

The human microbiome can produce metabolites that modulate insulin signaling. Type 2 diabetes patients have increased circulating concentrations of the microbially produced histidine metabolite, imidazole propionate (ImP) and administration of ImP in mice resulted in impaired glucose tolerance. Interestingly, the fecal microbiota of the patients had increased capacity to produce ImP, which is mediated by the bacterial enzyme urocanate reductase (UrdA). Here, we describe the X-ray structures of the ligand-binding domains of UrdA in four different states, representing the structural transitions along the catalytic reaction pathway of this unexplored enzyme linked to disease in humans. The structures in combination with functional data provide key insights into the mechanism of action of UrdA that open new possibilities for drug development strategies targeting type 2 diabetes. Imidazole propionate (ImP) produced by gut microbiota has been associated with type 2 diabetes. Here, the authors present crystal structures of the ImP biosynthesis enzyme urocanate reductase in four different states, providing molecular insights into its catalytic mechanism. [ABSTRACT FROM AUTHOR]

Featured Application: This comprehensive overview of drug-resistant tuberculosis will be useful for researchers to expand their knowledge beyond mechanisms other than chromosomal mutations, and for the development of novel drugs/drug combinations, hoping to shorten the therapy of the disease. The control of tuberculosis (TB) is hampered by the emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strains, defined as resistant to at least isoniazid and rifampin, the two bactericidal drugs essential for the treatment of the disease. Due to the worldwide estimate of almost half a million incident cases of MDR/rifampin-resistant TB, it is important to continuously update the knowledge on the mechanisms involved in the development of this phenomenon. Clinical, biological and microbiological reasons account for the generation of resistance, including: (i) nonadherence of patients to their therapy, and/or errors of physicians in therapy management, (ii) complexity and poor vascularization of granulomatous lesions, which obstruct drug distribution to some sites, resulting in resistance development, (iii) intrinsic drug resistance of tubercle bacilli, (iv) formation of non-replicating, drug-tolerant bacilli inside the granulomas, (v) development of mutations in Mtb genes, which are the most important molecular mechanisms of resistance. This review provides a comprehensive overview of these issues, and releases up-dated information on the therapeutic strategies recently endorsed and recommended by the World Health Organization to facilitate the clinical and microbiological management of drug-resistant TB at the global level, with attention also to the most recent diagnostic methods. [ABSTRACT FROM AUTHOR]

In the era of multidrug resistant (MDR) organisms, reliable efficacy testing of novel antimicrobials during developmental stages is of paramount concern prior to introduction in clinical trials. Unfortunately, interstrain variability is often underappreciated when appraising the efficacy of innovative antimicrobials as preclinical testing of a limited number of standardized strains in unvarying conditions does not account for the vastness and potential for hyperdiversity among and within microbial populations. In this review, the importance of accounting for interstrain variability's potential to impact breadth of novel drug efficacy evaluation in the early stages of drug development will be discussed. Additionally, testing under varying microenvironmental conditions that may influence drug efficacy will be discussed. Biofilm growth, the influence of polymicrobial growth, mechanisms of antimicrobial resistance, pH, anaerobic conditions, and other virulence factors are some of critical issues that require more attention and standardization during preclinical drug efficacy evaluation. Furthermore, potential solutions for addressing this issue in pre-clinical antimicrobial development are proposed via centralization of microbial characterization and drug target databases, testing of a large number of clinical strains, inclusion of mutator strains in testing and the use of growth parameter mathematical models for testing. [ABSTRACT FROM AUTHOR]

TargetingM. tuberculosis(Mtb) in latent form of infection is a major obstacle and big challenge in tuberculosis (TB) eradication by current chemotherapy. A better understanding of the physiology of Mtb and of the metabolic state of the bacillus during the dormancy, is a primary need in finding drug targets against non replicating persistent (NRP) form of the Mtb. Identification of potential drug targets against dormant state of Mtb is critically important to achieve the goal of complete eradication for shortening of anti-TB therapy. The metabolic processes functioning in dormant Mtb in providing cell viability and protecting Mtb from sterilization by the hostile environment can be explored as drug targets. This review discusses about the potential drug targets in dormant tubercle bacilli, anti-dormancy inhibitors and the strategies which can be pursued for maximizing success if these targets are exploited for killing the dormant bacilli. This has important implications as the currently available arsenal of drugs suffers from the demerit of achieving sterilizing killing of mycobacteria. This lacuna can be overcome if the proposed strategies for eliminating dormant bacteria are combined along with the existing treatment modalities for the extirpation of bacilli. [ABSTRACT FROM PUBLISHER]

The glycerol kinase ( GK) of African human trypanosomes is compartmentalized in their glycosomes. Unlike the host GK, which under physiological conditions catalyzes only the forward reaction ( ATP-dependent glycerol phosphorylation), trypanosome GK can additionally catalyze the reverse reaction. In fact, owing to this unique reverse catalysis, GK is potentially essential for the parasites survival in the human host, hence a promising drug target. The mechanism of its reverse catalysis was unknown; therefore, it was not clear if this ability was purely due to its localization in the organelles or whether structure-based catalytic differences also contribute. To investigate this lack of information, the X-ray crystal structure of this protein was determined up to 1.90 Å resolution, in its unligated form and in complex with three natural ligands. These data, in conjunction with results from structure-guided mutagenesis suggests that the trypanosome GK is possibly a transiently autophosphorylating threonine kinase, with the catalytic site formed by non-conserved residues. Our results provide a series of structural peculiarities of this enzyme, and gives unexpected insight into the reverse catalysis mechanism. Together, they provide an encouraging molecular framework for the development of trypanosome GK-specific inhibitors, which may lead to the design of new and safer trypanocidal drug(s). [ABSTRACT FROM AUTHOR]

Despite the introduction 40 years ago of the inexpensive and effective four-drug (isoniazid, rifampicin, pyrazinamide and ethambutol) treatment regimen, tuberculosis (TB) continues to cause considerable morbidity and mortality worldwide. For the first time since the 1960s, new and novel drugs and regimens for all forms of TB are emerging. Such regimens are likely to utilize both repurposed drugs and new chemical entities, and several of these regimens are now progressing through clinical trials. This article covers current concepts and recent advances in TB drug discovery and development, including an update of ongoing TB treatment trials, newer clinical trial designs, TB biomarkers and adjunct host-directed therapies. [ABSTRACT FROM AUTHOR]

McKellar, Q. A., Sanchez Bruni, S. F. Jones, D. G. Pharmacokinetic/pharmacodynamic relationships of antimicrobial drugs used in veterinary medicine.J. vet. Pharmacol. Therap.27, 503–514.The rise in incidence of antimicrobial resistance, consumer demands and improved understanding of antimicrobial action has encouraged international agencies to review the use of antimicrobial drugs. More detailed understanding of relationships between the pharmacokinetics (PK) of antimicrobial drugs in target animal species and their action on target pathogens [pharmacodynamics (PD)] has led to greater sophistication in design of dosage schedules which improve the activity and reduce the selection pressure for resistance in antimicrobial therapy. This, in turn, may be informative in the pharmaceutical development of antimicrobial drugs and in their selection and clinical utility. PK/PD relationships between area under the concentration time curve from zero to 24 h (AUC0--24) and minimum inhibitory concentration (MIC), maximum plasma concentration (Cmax) andMICand time during which plasma concentrations exceed theMIChave been particularly useful in optimizing efficacy and minimizing resistance. Antimicrobial drugs have been classified as concentration-dependent where increasing concentrations at the locus of infection improve bacterial kill, or time-dependent where exceeding theMICfor a prolonged percentage of the inter-dosing interval correlates with improved efficacy. For the latter group increasing the absolute concentration obtained above a threshold does not improve efficacy. The PK/PD relationship for each group of antimicrobial drugs is‘bug and drug’ specific, although ratios of 125 forAUC0--24:MICand 10 forCmax:MIChave been recommended to achieve high efficacy for concentration-dependent antimicrobial drugs, and exceedingMICby 1–5 multiples for between 40 and 100% of the inter-dosing interval is appropriate for most time-dependent agents. Fluoroquinolones, aminoglycosides and metronidazole are concentration-dependent and beta-lactams, macrolides, lincosamides and glycopeptides are time-dependent. For drugs of other classes there is limited and conflicting information on their classification. Resistance selection may be reduced for concentration-dependent antimicrobials by achieving anAUC0--24:MICratio of greater than 100 or aCmax:MICratio of greater than 8. The relationships between time greater thanMICand resistance selection for time-dependent antimicrobials have not been well characterized. [ABSTRACT FROM AUTHOR]