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International Journal of Molecular... Aug 2023Peripheral nerve injuries have far-reaching implications for individuals and society, leading to functional impairments, prolonged rehabilitation, and substantial... (Review)
Review
Peripheral nerve injuries have far-reaching implications for individuals and society, leading to functional impairments, prolonged rehabilitation, and substantial socioeconomic burdens. Tacrolimus, a potent immunosuppressive drug known for its neuroregenerative properties, has emerged in experimental studies as a promising candidate to accelerate nerve fiber regeneration. This review investigates the therapeutic potential of tacrolimus by exploring the postulated mechanisms of action in relation to biological barriers to nerve injury recovery. By mapping both the preclinical and clinical evidence, the benefits and drawbacks of systemic tacrolimus administration and novel delivery systems for localized tacrolimus delivery after nerve injury are elucidated. Through synthesizing the current evidence, identifying practical barriers for clinical translation, and discussing potential strategies to overcome the translational gap, this review provides insights into the translational perspectives of tacrolimus as an adjunct therapy for nerve regeneration.
Topics: Humans; Tacrolimus; Immunosuppressive Agents; Administration, Cutaneous; Medicine; Nerve Regeneration
PubMed: 37628951
DOI: 10.3390/ijms241612771 -
Biomolecules Oct 2023Invasive fungal infections present a significant risk to human health. The current arsenal of antifungal drugs is hindered by drug resistance, limited antifungal range,... (Review)
Review
Invasive fungal infections present a significant risk to human health. The current arsenal of antifungal drugs is hindered by drug resistance, limited antifungal range, inadequate safety profiles, and low oral bioavailability. Consequently, there is an urgent imperative to develop novel antifungal medications for clinical application. This comprehensive review provides a summary of the antifungal properties and mechanisms exhibited by natural polyketides, encompassing macrolide polyethers, polyether polyketides, xanthone polyketides, linear polyketides, hybrid polyketide non-ribosomal peptides, and pyridine derivatives. Investigating natural polyketide compounds and their derivatives has demonstrated their remarkable efficacy and promising clinical application as antifungal agents.
Topics: Humans; Antifungal Agents; Polyketides; Macrolides; Peptides
PubMed: 38002254
DOI: 10.3390/biom13111572 -
Trends in Microbiology Dec 2023Antibiotics often contain ester bonds. The macrocyclic lactones of macrolides are pre-eminent examples in which ester bonds are essential to the form and function of...
Antibiotics often contain ester bonds. The macrocyclic lactones of macrolides are pre-eminent examples in which ester bonds are essential to the form and function of antibiotics. Bacterial macrolide esterases that hydrolyze these macrocyclic lactones to confer antimicrobial resistance (AMR) are the topic of this forum. We provide insight into their role in agricultural systems and discuss their emergence and their potential extensibility to bioremediation efforts.
Topics: Macrolides; Esterases; Anti-Bacterial Agents; Lactones; Esters; Drug Resistance, Bacterial
PubMed: 37689489
DOI: 10.1016/j.tim.2023.08.008 -
Chembiochem : a European Journal of... Mar 2024Lincosamides are naturally occurring antibiotics isolated from Streptomyces sp. Currently, lincomycin A and its semisynthetic analogue clindamycin are used as clinical... (Review)
Review
Lincosamides are naturally occurring antibiotics isolated from Streptomyces sp. Currently, lincomycin A and its semisynthetic analogue clindamycin are used as clinical drugs. Due to their unique structures and remarkable biological activities, derivatizations of lincosamides via semi-synthesis and biosynthetic studies have been reported. This review summarizes the structures and biological activities of lincosamides, and the recent studies of lincosamide biosynthetic enzymes.
Topics: Anti-Bacterial Agents; Lincosamides; Lincomycin; Macrolides
PubMed: 38165257
DOI: 10.1002/cbic.202300840 -
Respiratory Medicine Oct 2023Macrolide-resistant Mycobacterium avium complex (MAC) disease is very difficult to cure. Macrolide-resistance emerges in patients and is largely preventable by...
BACKGROUND
Macrolide-resistant Mycobacterium avium complex (MAC) disease is very difficult to cure. Macrolide-resistance emerges in patients and is largely preventable by appropriate screening and treatment practices.
METHODS
Patients with macrolide-resistant MAC isolates between March 2019 and March 2022 were retrieved from the mycobacteriology reference laboratory database at Radboudumc, Nijmegen, the Netherlands. Clinical consultation reports were extracted from the database to assess the cause of macrolide resistance.
RESULTS
Sixteen patients with macrolide-resistant MAC disease were included, from a total of 815 patients with MAC isolates (2%); Macrolide monotherapy in bronchiectasis or CF was the most frequent cause of development of macrolide-resistance MAC disease (n = 8; 50%). Short (n = 3; mean duration 9 months, range 6-12) or guideline non-compliant (n = 2) treatment regimens and patient non-adherence (n = 2) were other key causes of macrolide-resistance.
CONCLUSIONS
Macrolide monotherapy after inappropriate screening is the most frequent cause of macrolide-resistant Mycobacterium avium complex disease in the Netherlands. Educational efforts are needed to prevent this.
Topics: Humans; Mycobacterium avium Complex; Anti-Bacterial Agents; Macrolides; Mycobacterium avium-intracellulare Infection; Drug Resistance, Bacterial; Lung Diseases
PubMed: 37481170
DOI: 10.1016/j.rmed.2023.107366 -
Nature Communications Jul 2023The ever-growing rise of antibiotic resistance among bacterial pathogens is one of the top healthcare threats today. Although combination antibiotic therapies represent...
The ever-growing rise of antibiotic resistance among bacterial pathogens is one of the top healthcare threats today. Although combination antibiotic therapies represent a potential approach to more efficiently combat infections caused by susceptible and drug-resistant bacteria, only a few known drug pairs exhibit synergy/cooperativity in killing bacteria. Here, we discover that well-known ribosomal antibiotics, hygromycin A (HygA) and macrolides, which target peptidyl transferase center and peptide exit tunnel, respectively, can act cooperatively against susceptible and drug-resistant bacteria. Remarkably, HygA slows down macrolide dissociation from the ribosome by 60-fold and enhances the otherwise weak antimicrobial activity of the newest-generation macrolide drugs known as ketolides against macrolide-resistant bacteria. By determining a set of high-resolution X-ray crystal structures of drug-sensitive wild-type and macrolide-resistant Erm-methylated 70S ribosomes in complex with three HygA-macrolide pairs, we provide a structural rationale for the binding cooperativity of these drugs and also uncover the molecular mechanism of overcoming Erm-type resistance by macrolides acting together with hygromycin A. Altogether our structural, biochemical, and microbiological findings lay the foundation for the subsequent development of synergistic antibiotic tandems with improved bactericidal properties against drug-resistant pathogens, including those expressing erm genes.
Topics: Macrolides; Anti-Bacterial Agents; Cinnamates; Hygromycin B; Ketolides; Protein Synthesis Inhibitors; Bacteria; Drug Resistance, Bacterial
PubMed: 37452045
DOI: 10.1038/s41467-023-39653-5 -
Clinical Interventions in Aging 2023Alzheimer's disease (AD) is a sporadic or familial neurodegenerative disease of insidious onset with progressive cognitive decline. Although numerous studies have been... (Review)
Review
Alzheimer's disease (AD) is a sporadic or familial neurodegenerative disease of insidious onset with progressive cognitive decline. Although numerous studies have been conducted or are underway on AD, there are still no effective drugs to reverse the pathological features and clinical manifestations of AD. Rapamycin is a macrolide antibiotic produced by . As a classical mechanistic target of rapamycin (mTOR) inhibitor, rapamycin has been shown to be beneficial in a variety of AD mouse and cells models, both before the onset of disease symptoms and the early stage of disease. Although many basic studies have demonstrated the therapeutic effects of rapamycin in AD, many questions and controversies remain. This may be due to the variability of experimental models, different modes of administration, dose, timing, frequency, and the availability of drug-targeting vehicles. Rapamycin may delay the development of AD by reducing β-amyloid (Aβ) deposition, inhibiting tau protein hyperphosphorylation, maintaining brain function in gene carriers, clearing chronic inflammation, and improving cognitive dysfunction. It is thus expected to be one of the candidates for the treatment of Alzheimer's disease.
Topics: Mice; Animals; Alzheimer Disease; Sirolimus; Neurodegenerative Diseases; Amyloid beta-Peptides; tau Proteins; Cognitive Dysfunction
PubMed: 37810956
DOI: 10.2147/CIA.S429440 -
Microbiology Spectrum Dec 2023This study first reported the effector kinetics of the new non-fluorinated quinolone, nemonoxacin, against macrolide-resistant (MRMP) and macrolide susceptible (MSMP)...
This study first reported the effector kinetics of the new non-fluorinated quinolone, nemonoxacin, against macrolide-resistant (MRMP) and macrolide susceptible (MSMP) strains along with other antimicrobial agents. The time-kill assays and pharmacodynamic analysis showed that nemonoxacin has significant mycoplasmacidal activity against MRMP and MSMP. This study paves the road to establish appropriate dosing protocols of a new antimicrobial drug for children infected with .
Topics: Child; Humans; Mycoplasma pneumoniae; Pneumonia, Mycoplasma; Anti-Bacterial Agents; Quinolones; Macrolides; Drug Resistance, Bacterial; Microbial Sensitivity Tests
PubMed: 37975686
DOI: 10.1128/spectrum.02431-23 -
Transplantation and Cellular Therapy Sep 2023Belumosudil (BEL) is a novel Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor approved for the treatment of chronic graft-versus-host disease...
Belumosudil (BEL) is a novel Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor approved for the treatment of chronic graft-versus-host disease (cGVHD) in patients who have failed 2 or more prior lines of systemic therapy. Although the pharmacokinetic effects of BEL on other immunosuppressive (IS) agents have not been clinically evaluated, in vitro data indicate that BEL may have possible interactions with drugs with a narrow therapeutic index used to treat cGVHD, such as tacrolimus, sirolimus, and cyclosporine, through cytochrome P450 (CYP3A) and p-glycoprotein interactions. Further evaluation of these potential interactions is warranted to optimize the safety and effectiveness of these medications when combined with BEL. In this study, we investigated the potential effects of BEL on sirolimus and tacrolimus levels when used concurrently by assessing changes in IS levels after the addition of BEL. This retrospective single-center study of patients who started BEL while on tacrolimus and/or sirolimus between February 1, 2019, to February 1, 2023, included patients who had IS levels measured at baseline prior to starting BEL and at least 1 subsequent IS measurement to assess changes over time. The primary endpoint was the concentration-dose (C/D) ratio analyzed before and after the addition of BEL. Secondary endpoints included the incidence of IS levels outside of the therapeutic range (subtherapeutic or supratherapeutic) and mean dosage changes over time. Thirty-seven patients met our eligibility criteria and were included in this analysis. Patients taking sirolimus (n = 30) or tacrolimus (n = 16) concurrently with BEL had a statistically significant increase in the C/D ratio (sirolimus recipients, 160% [P < .001]; tacrolimus recipients, 113% [P = .013]) between the pre-BEL and final post-BEL assessments. The C/D ratios for both tacrolimus and sirolimus recipients continued to increase at several time points after initiation of BEL, indicating that multiple drug dosage adjustments may be required. After BEL initiation, 19% of tacrolimus levels and 57% of sirolimus levels were supratherapeutic. Despite dosage adjustments, 27% of tacrolimus levels were supratherapeutic at both the second and third assessments after starting BEL, and 28% and 30% of sirolimus levels were supratherapeutic at these 2 time points, respectively. All 12 of the patients who discontinued BEL during the study period (100%) showed a return to their baseline C/D ratio, confirming that the C/D ratio change can be attributed to BEL. The impact of BEL on IS levels is clinically significant, warranting dosage adjustments of concurrent medications. A significant number of patients taking sirolimus with BEL had levels >15 ng/mL during the study period, indicating a potential risk for toxicity if this interaction is unmonitored. We recommend empiric dose reductions of 25% for tacrolimus and 25% to 50% for sirolimus when adding BEL, as well as close monitoring of IS levels during the initial weeks of BEL therapy. Future studies are warranted to better describe the impact of BEL on patients taking CYP3A inhibitors.
Topics: Humans; Tacrolimus; Graft vs Host Disease; Bronchiolitis Obliterans Syndrome; Retrospective Studies; Immunosuppressive Agents; Sirolimus; Immunosuppression Therapy
PubMed: 37355201
DOI: 10.1016/j.jtct.2023.06.011 -
Aging Cell Aug 2023Rapamycin is a macrolide antibiotic that functions as an immunosuppressive and anti-cancer agent, and displays robust anti-ageing effects in multiple organisms including...
Rapamycin is a macrolide antibiotic that functions as an immunosuppressive and anti-cancer agent, and displays robust anti-ageing effects in multiple organisms including humans. Importantly, rapamycin analogues (rapalogs) are of clinical importance against certain cancer types and neurodevelopmental diseases. Although rapamycin is widely perceived as an allosteric inhibitor of mTOR (mechanistic target of rapamycin), the master regulator of cellular and organismal physiology, its specificity has not been thoroughly evaluated so far. In fact, previous studies in cells and in mice hinted that rapamycin may be also acting independently from mTOR to influence various cellular processes. Here, we generated a gene-edited cell line that expresses a rapamycin-resistant mTOR mutant (mTOR ) and assessed the effects of rapamycin treatment on the transcriptome and proteome of control or mTOR -expressing cells. Our data reveal a striking specificity of rapamycin towards mTOR, demonstrated by virtually no changes in mRNA or protein levels in rapamycin-treated mTOR cells, even following prolonged drug treatment. Overall, this study provides the first unbiased and conclusive assessment of rapamycin's specificity, with potential implications for ageing research and human therapeutics.
Topics: Mice; Humans; Animals; MTOR Inhibitors; Signal Transduction; Cell Line, Tumor; TOR Serine-Threonine Kinases; Sirolimus; Mechanistic Target of Rapamycin Complex 1
PubMed: 37222020
DOI: 10.1111/acel.13888