-
Scientific Reports Nov 2023The prevalence of Mycobacterium avium complex-pulmonary disease (MAC-PD) has become a growing concern worldwide, and current treatments involving macrolides...
The prevalence of Mycobacterium avium complex-pulmonary disease (MAC-PD) has become a growing concern worldwide, and current treatments involving macrolides (clarithromycin [CLR] or azithromycin), ethambutol, and rifampicin have limited success, highlighting the need for better therapeutic strategies. Recently, oxazolidinone drugs have been identified as novel anti-tuberculosis drugs effective against drug-resistant M. tuberculosis. However, the effects of these drugs against MAC are still controversial due to limited data. Here, we first evaluated the intracellular anti-MAC activities of two oxazolidinone drugs, linezolid (LZD) and delpazolid (DZD), against 10 macrolide-susceptible MAC strains and one macrolide-resistant M. avium strain in murine bone marrow-derived macrophages (BMDMs) and found that both drugs demonstrated similar potential. The synergistic efficacies with CLR were then determined in a chronic progressive MAC-PD murine model by initiating a 4-week treatment at 8 weeks post-infection. Upon assessment of bacterial burdens and inflamed lesions, oxazolidinone drugs exhibited no anti-MAC effect, and there was no significant difference in the synergistic effect of CLR between LZD and DZD. These findings suggest that oxazolidinone drugs inhibit intracellular bacterial growth, even against macrolide-resistant MAC, but their clinical application requires further consideration.
Topics: Humans; Mice; Animals; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Oxazolidinones; Anti-Bacterial Agents; Antitubercular Agents; Clarithromycin; Macrolides; Lung Diseases
PubMed: 37996500
DOI: 10.1038/s41598-023-48001-y -
Molecular Pharmaceutics Dec 2023Macrolides are widely used for the long-term treatment of infections and chronic inflammatory diseases. The pharmacokinetic features of macrolides include extensive...
Macrolide and Ketolide Antibiotics Inhibit the Cytotoxic Effect of Trastuzumab Emtansine in HER2-Positive Breast Cancer Cells: Implication of a Potential Drug-ADC Interaction in Cancer Chemotherapy.
Macrolides are widely used for the long-term treatment of infections and chronic inflammatory diseases. The pharmacokinetic features of macrolides include extensive tissue distribution because of favorable membrane permeability and accumulation within lysosomes. Trastuzumab emtansine (T-DM1), a HER2-targeting antibody-drug conjugate (ADC), is catabolized in the lysosomes, where Lys-SMCC-DM1, a potent cytotoxic agent, is processed by proteinase degradation and subsequently released from the lysosomes to the cytoplasm through the lysosomal membrane transporter SLC46A3, resulting in an antitumor effect. We recently demonstrated that erythromycin and clarithromycin inhibit SLC46A3 and attenuate the cytotoxicity of T-DM1; however, the effect of other macrolides and ketolides has not been determined. In this study, we evaluated the effect of macrolide and ketolide antibiotics on T-DM1 cytotoxicity in a human breast cancer cell line, KPL-4. Macrolides used in the clinic, such as roxithromycin, azithromycin, and josamycin, as well as solithromycin, a ketolide under clinical development, significantly attenuated T-DM1 cytotoxicity in addition to erythromycin and clarithromycin. Of these, azithromycin was the most potent inhibitor of T-DM1 efficacy. These antibiotics significantly inhibited the transport function of SLC46A3 in a concentration-dependent manner. Moreover, these compounds extensively accumulated in the lysosomes at the levels estimated to be 0.41-13.6 mM when cells were incubated with them at a 2 μM concentration. The immunofluorescence staining of trastuzumab revealed that azithromycin and solithromycin inhibit the degradation of T-DM1 in the lysosomes. These results suggest that the attenuation of T-DM1 cytotoxicity by macrolide and ketolide antibiotics involves their lysosomal accumulation and results in their greater lysosomal concentrations to inhibit the SLC46A3 function and T-DM1 degradation. This suggests a potential drug-ADC interaction during cancer chemotherapy.
Topics: Humans; Female; Ado-Trastuzumab Emtansine; Breast Neoplasms; Ketolides; Immunoconjugates; Azithromycin; Clarithromycin; Maytansine; Receptor, ErbB-2; Antibodies, Monoclonal, Humanized; Trastuzumab; Antineoplastic Agents; Lysosomes; Anti-Bacterial Agents
PubMed: 37971309
DOI: 10.1021/acs.molpharmaceut.3c00490 -
Journal of Biochemical and Molecular... Sep 2023During the period of COVID-19, the occurrences of mucormycosis in immunocompromised patients have increased significantly. Mucormycosis (black fungus) is a rare and... (Review)
Review
During the period of COVID-19, the occurrences of mucormycosis in immunocompromised patients have increased significantly. Mucormycosis (black fungus) is a rare and rapidly progressing fungal infection associated with high mortality and morbidity in India as well as globally. The causative agents for this infection are collectively called mucoromycetes which are the members of the order Mucorales. The diagnosis of the infection needs to be performed as soon as the occurrence of clinical symptoms which differs with types of Mucorales infection. Imaging techniques magnetic resonance imaging or computed tomography scan, culture testing, and microscopy are the approaches for the diagnosis. After the diagnosis of the infection is confirmed, rapid action is needed for the treatment in the form of antifungal therapy or surgery depending upon the severity of the infection. Delaying in treatment declines the chances of survival. In antifungal therapy, there are two approaches first-line therapy (monotherapy) and combination therapy. Amphotericin B (1) and isavuconazole (2) are the drugs of choice for first-line therapy in the treatment of mucormycosis. Salvage therapy with posaconazole (3) and deferasirox (4) is another approach for patients who are not responsible for any other therapy. Adjunctive therapy is also used in the treatment of mucormycosis along with first-line therapy, which involves hyperbaric oxygen and cytokine therapy. There are some drugs like VT-1161 (5) and APX001A (6), Colistin, SCH 42427, and PC1244 that are under clinical trials. Despite all these approaches, none can be 100% successful in giving results. Therefore, new medications with favorable or little side effects are required for the treatment of mucormycosis.
Topics: Humans; Antifungal Agents; Mucormycosis; COVID-19; Amphotericin B; Mucorales
PubMed: 37345721
DOI: 10.1002/jbt.23417 -
International Journal of Nanomedicine 2023Macrolide drugs are among the broad-spectrum antibiotics that are considered as "miracle drugs" against infectious diseases that lead to higher morbidity and mortality... (Review)
Review
Macrolide drugs are among the broad-spectrum antibiotics that are considered as "miracle drugs" against infectious diseases that lead to higher morbidity and mortality rates. Nevertheless, their effectiveness is currently at risk owing to the presence of devastating, antimicrobial-resistant microbes. In view of this challenge, nanotechnology-driven innovations are currently being anticipated for promising approaches to overcome antimicrobial resistance. Nowadays, various nanostructures are being developed for the delivery of antimicrobials to counter drug-resistant microbial strains through different mechanisms. Metallic nanoparticle-based delivery of macrolides, particularly using silver and gold nanoparticles (AgNPs & AuNPs), demonstrated a promising outcome with worthy stability, oxidation resistance, and biocompatibility. Similarly, macrolide-conjugated magnetic NPs resulted in an augmented antimicrobial activity and reduced bacterial cell viability against resistant microbes. Liposomal delivery of macrolides also showed favorable synergistic antimicrobial activities in vitro against resistant strains. Loading macrolide drugs into various polymeric nanomaterials resulted in an enhanced zone of inhibition. Intercalated nanomaterials also conveyed an outstanding macrolide delivery characteristic with efficient targeting and controlled drug release against infectious microbes. This review abridges several nano-based delivery approaches for macrolide drugs along with their recent achievements, challenges, and future perspectives.
Topics: Gold; Macrolides; Metal Nanoparticles; Anti-Bacterial Agents; Nanostructures
PubMed: 37732155
DOI: 10.2147/IJN.S418588 -
Nature Communications Jul 2023Antibiotic resistance ABC-Fs (ARE ABC-Fs) are translation factors that provide resistance against clinically important ribosome-targeting antibiotics which are...
Antibiotic resistance ABC-Fs (ARE ABC-Fs) are translation factors that provide resistance against clinically important ribosome-targeting antibiotics which are proliferating among pathogens. Here, we combine genetic and structural approaches to determine the regulation of streptococcal ARE ABC-F gene msrD in response to macrolide exposure. We show that binding of cladinose-containing macrolides to the ribosome prompts insertion of the leader peptide MsrDL into a crevice of the ribosomal exit tunnel, which is conserved throughout bacteria and eukaryotes. This leads to a local rearrangement of the 23 S rRNA that prevents peptide bond formation and accommodation of release factors. The stalled ribosome obstructs the formation of a Rho-independent terminator structure that prevents msrD transcriptional attenuation. Erythromycin induction of msrD expression via MsrDL, is suppressed by ectopic expression of mrsD, but not by mutants which do not provide antibiotic resistance, showing correlation between MsrD function in antibiotic resistance and its action on this stalled complex.
Topics: Humans; Anti-Bacterial Agents; Drug Resistance, Bacterial; Macrolides; Abducens Nerve Diseases; Accommodation, Ocular
PubMed: 37393329
DOI: 10.1038/s41467-023-39553-8 -
ELife Nov 2023accounts for the majority of over 600,000 malaria-associated deaths annually. Parasites resistant to nearly all antimalarials have emerged and the need for drugs with...
accounts for the majority of over 600,000 malaria-associated deaths annually. Parasites resistant to nearly all antimalarials have emerged and the need for drugs with alternative modes of action is thus undoubted. The FK506-binding protein FKBP35 has gained attention as a promising drug target due to its high affinity to the macrolide compound FK506 (tacrolimus). Whilst there is considerable interest in targeting FKBP35 with small molecules, a genetic validation of this factor as a drug target is missing and its function in parasite biology remains elusive. Here, we show that limiting FKBP35 levels are lethal to and result in a delayed death-like phenotype that is characterized by defective ribosome homeostasis and stalled protein synthesis. Our data furthermore suggest that FK506, unlike the action of this drug in model organisms, exerts its antiproliferative activity in a FKBP35-independent manner and, using cellular thermal shift assays, we identify putative FK506-targets beyond FKBP35. In addition to revealing first insights into the function of FKBP35, our results show that FKBP-binding drugs can adopt non-canonical modes of action - with major implications for the development of FK506-derived molecules active against parasites and other eukaryotic pathogens.
Topics: Humans; Antimalarials; Tacrolimus; Anti-Bacterial Agents; Drug Delivery Systems; Homeostasis; Malaria, Falciparum; Tacrolimus Binding Proteins
PubMed: 37934560
DOI: 10.7554/eLife.86975 -
Biochemical Pharmacology Jul 2023Corneal diseases affect 4.2 million people worldwide and are a leading cause of vision impairment and blindness. Current treatments for corneal diseases, such as... (Review)
Review
Corneal diseases affect 4.2 million people worldwide and are a leading cause of vision impairment and blindness. Current treatments for corneal diseases, such as antibiotics, steroids, and surgical interventions, have numerous disadvantages and challenges. Thus, there is an urgent need for more effective therapies. Although the pathogenesis of corneal diseases is not fully understood, it is known that injury caused by various stresses and postinjury healing, such as epithelial renewal, inflammation, stromal fibrosis, and neovascularization, are highly involved. Mammalian target of rapamycin (mTOR) is a key regulator of cell growth, metabolism, and the immune response. Recent studies have revealed that activation of mTOR signalling extensively contributes to the pathogenesis of various corneal diseases, and inhibition of mTOR with rapamycin achieves promising outcomes, supporting the potential of mTOR as a therapeutic target. In this review, we detail the function of mTOR in corneal diseases and how these characteristics contribute to disease treatment using mTOR-targeted drugs.
Topics: Humans; Corneal Diseases; Inflammation; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 37217140
DOI: 10.1016/j.bcp.2023.115620 -
International Journal of Gynecological... Apr 2024
Topics: Humans; Female; Antibodies, Monoclonal, Humanized; Maytansine; Immunoconjugates; Ovarian Neoplasms
PubMed: 38388176
DOI: 10.1136/ijgc-2024-005400 -
Alternative Therapies in Health and... Nov 2023To analyze the use of antimicrobial drugs in patients during the COVID-19 pandemic. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To analyze the use of antimicrobial drugs in patients during the COVID-19 pandemic.
METHODS
We searched for literature about antimicrobial treatment in COVID-19 patients through the Cochrane Library, Embase, PubMed, the Chinese biomedical literature database, CNKI, the Chinese journal full-text database, Wanfang, and Vipu. The quality evaluation of the literature was performed by Jadad's quality score.
RESULTS
A total of three articles reported on ivermectin treatment in patients with COVID-19, and the Meta-analysis showed no clinical and statistical heterogeneity among the studies (I2 = 15%, P = .31), a fixed effect model was used to incorporate effect sizes. The clinical effect of the observed group was not different from the control group (P = .16). None of the three ivermectin articles with clinical effect as the effect indicator showed a significant difference (P > .05), suggesting no publication bias. A total of four publications reported the treatment with azithromycin in patients with COVID-19, and the Meta-analysis showed no clinical and statistical heterogeneity between the studies (I2 = 0%, P = .88), using a fixed-effect model to incorporate the effect sizes. The clinical effect of the observed group was not different from the control group (P = .57). None of the four azithromycin articles with a clinical effect as the effect index was statistically significant (P > .05), suggesting no publication bias.
CONCLUSION
During the COVID-19 pandemic, the patient's use of antibiotics does not significantly improve clinical efficacy, so antibiotic use is recommended only for patients with complicated bacterial infections.
Topics: Humans; COVID-19; Azithromycin; Pandemics; Ivermectin; Anti-Bacterial Agents
PubMed: 37708540
DOI: No ID Found -
The Journal of Dermatological Treatment Dec 2023Atopic dermatitis (AD) exhibits difference in immune polarization between Caucasians and Asian races due to which an evaluation of the efficacy and safety of... (Comparative Study)
Comparative Study Randomized Controlled Trial
INTRODUCTION
Atopic dermatitis (AD) exhibits difference in immune polarization between Caucasians and Asian races due to which an evaluation of the efficacy and safety of Pimecrolimus (PIM) in Asian population is called for. The current study addresses the need a sub-group analysis of the PETITE study (NCT00120523) to evaluate the safety and efficacy of PIM in Chinese infants.
MATERIALS AND METHODS
Patients with AD (≥3 months-<12 months of age) were randomized in a 1:1 ratio to either PIM 1% cream or topical corticosteroids (TCS). The primary endpoint was safety. The secondary endpoint was efficacy.
RESULTS
120 patients were randomized to either PIM 1% or TCS ( = 61 for PIM, = 59 for TCS). The most often reported adverse events were reported by similar proportions of patients treated with PIM or TCS. There was a progressive increase in overall IGA treatment success in infants treated with PIM (82.9%, < .05, 95% CI: 70.4, 95.3) after 26 weeks which was comparable to the TCS group (88.5%, < .05, 95% CI: 79.8, 97.1).
CONCLUSION
PIM showed an early and sustained efficacy in the Chinese sub-population with a substantial corticosteroid-sparing effect in patients with AD.
Topics: Humans; Infant; Dermatitis, Atopic; Dermatologic Agents; East Asian People; Tacrolimus; Treatment Outcome; Administration, Topical; Glucocorticoids; Skin Cream
PubMed: 37394952
DOI: 10.1080/09546634.2023.2229464