دورية أكاديمية
Ethambutol and meropenem/clavulanate synergy promotes enhanced extracellular and intracellular killing of Mycobacterium tuberculosis .
| العنوان: | Ethambutol and meropenem/clavulanate synergy promotes enhanced extracellular and intracellular killing of Mycobacterium tuberculosis . |
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| المؤلفون: | Olivença F; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal., Pires D; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.; Universidade Católica Portuguesa, Católica Medical School, Centre for Interdisciplinary Research in Health, Lisbon, Portugal., Silveiro C; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal., Gama B; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal., Holtreman F; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal., Anes E; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal., Catalão MJ; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal. |
| المصدر: | Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2024 Apr 03; Vol. 68 (4), pp. e0158623. Date of Electronic Publication: 2024 Feb 27. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 0315061 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-6596 (Electronic) Linking ISSN: 00664804 NLM ISO Abbreviation: Antimicrob Agents Chemother Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, American Society for Microbiology |
| مواضيع طبية MeSH: | Mycobacterium tuberculosis* , Tuberculosis, Multidrug-Resistant*/drug therapy , Tuberculosis*/microbiology, Humans ; Ethambutol/pharmacology ; Ethambutol/therapeutic use ; Meropenem/pharmacology ; Meropenem/therapeutic use ; Clavulanic Acid/pharmacology ; Antitubercular Agents/pharmacology ; Antitubercular Agents/therapeutic use ; Carbapenems/pharmacology ; beta-Lactams/pharmacology ; beta-Lactams/therapeutic use ; Microbial Sensitivity Tests |
| مستخلص: | Increasing evidence supports the repositioning of beta-lactams for tuberculosis (TB) therapy, but further research on their interaction with conventional anti-TB agents is still warranted. Moreover, the complex cell envelope of Mycobacterium tuberculosis ( Mtb ) may pose an additional obstacle to beta-lactam diffusion. In this context, we aimed to identify synergies between beta-lactams and anti-TB drugs ethambutol (EMB) and isoniazid (INH) by assessing antimicrobial effects, intracellular activity, and immune responses. Checkerboard assays with H37Rv and eight clinical isolates, including four drug-resistant strains, exposed that only treatments containing EMB and beta-lactams achieved synergistic effects. Meanwhile, the standard EMB and INH association failed to produce any synergy. In Mtb -infected THP-1 macrophages, combinations of EMB with increasing meropenem (MEM) concentrations consistently displayed superior killing activities over the individual antibiotics. Flow cytometry with BODIPY FL vancomycin, which binds directly to the peptidoglycan (PG), confirmed an increased exposure of this layer after co-treatment. This was reinforced by the high IL-1β secretion levels found in infected macrophages after incubation with MEM concentrations above 5 mg/L, indicating an exposure of the host innate response sensors to pathogen-associated molecular patterns in the PG. Our findings show that the proposed impaired access of beta-lactams to periplasmic transpeptidases is counteracted by concomitant administration with EMB. The efficiency of this combination may be attributed to the synchronized inhibition of arabinogalactan and PG synthesis, two key cell wall components. Given that beta-lactams exhibit a time-dependent bactericidal activity, a more effective pathogen recognition and killing prompted by this association may be highly beneficial to optimize TB regimens containing carbapenems.IMPORTANCEAddressing drug-resistant tuberculosis with existing therapies is challenging and the treatment success rate is lower when compared to drug-susceptible infection. This study demonstrates that pairing beta-lactams with ethambutol (EMB) significantly improves their efficacy against Mycobacterium tuberculosis ( Mtb ). The presence of EMB enhances beta-lactam access through the cell wall, which may translate into a prolonged contact between the drug and its targets at a concentration that effectively kills the pathogen. Importantly, we showed that the effects of the EMB and meropenem (MEM)/clavulanate combination were maintained intracellularly. These results are of high significance considering that the time above the minimum inhibitory concentration is the main determinant of beta-lactam efficacy. Moreover, a correlation was established between incubation with higher MEM concentrations during macrophage infection and increased IL-1β secretion. This finding unveils a previously overlooked aspect of carbapenem repurposing against tuberculosis, as certain Mtb strains suppress the secretion of this key pro-inflammatory cytokine to evade host surveillance. Competing Interests: The authors declare no conflict of interest. |
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| معلومات مُعتمدة: | PTDC/BIA-MIC/31233/2017 MEC | Fundação para a Ciência e a Tecnologia (FCT); ESCMID Research Grant 2018 European Society of Clinical Microbiology and Infectious Diseases (ESCMID); SFRH/BD/136853/2018 MEC | Fundação para a Ciência e a Tecnologia (FCT); 2021.05446.BD MEC | Fundação para a Ciência e a Tecnologia (FCT) |
| فهرسة مساهمة: | Keywords: Mycobacterium tuberculosis; antibiotic synergy; antimicrobial resistance; carbapenems |
| المشرفين على المادة: | 8G167061QZ (Ethambutol) FV9J3JU8B1 (Meropenem) 23521W1S24 (Clavulanic Acid) 0 (Antitubercular Agents) 0 (Carbapenems) 0 (beta-Lactams) |
| تواريخ الأحداث: | Date Created: 20240227 Date Completed: 20240404 Latest Revision: 20240405 |
| رمز التحديث: | 20240405 |
| مُعرف محوري في PubMed: | PMC10989012 |
| DOI: | 10.1128/aac.01586-23 |
| PMID: | 38411952 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1098-6596 |
|---|---|
| DOI: | 10.1128/aac.01586-23 |