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Trends in Biochemical Sciences Sep 2018Macrolide antibiotics inhibit protein synthesis by targeting the bacterial ribosome. They bind at the nascent peptide exit tunnel and partially occlude it. Thus,... (Review)
Review
Macrolide antibiotics inhibit protein synthesis by targeting the bacterial ribosome. They bind at the nascent peptide exit tunnel and partially occlude it. Thus, macrolides have been viewed as 'tunnel plugs' that stop the synthesis of every protein. More recent evidence, however, demonstrates that macrolides selectively inhibit the translation of a subset of cellular proteins, and that their action crucially depends on the nascent protein sequence and on the antibiotic structure. Therefore, macrolides emerge as modulators of translation rather than as global inhibitors of protein synthesis. The context-specific action of macrolides is the basis for regulating the expression of resistance genes. Understanding the details of the mechanism of macrolide action may inform rational design of new drugs and unveil important principles of translation regulation.
Topics: Anti-Bacterial Agents; Macrolides; Protein Biosynthesis
PubMed: 30054232
DOI: 10.1016/j.tibs.2018.06.011 -
The Laryngoscope Jan 2018To investigate the potential association of macrolide antibiotics with sensorineural hearing loss (SNHL) and which agents and dosage may be related. To evaluate whether... (Review)
Review
OBJECTIVES
To investigate the potential association of macrolide antibiotics with sensorineural hearing loss (SNHL) and which agents and dosage may be related. To evaluate whether an optimal treatment exists for reversing SNHL that occurs after macrolide therapy.
STUDY DESIGN
Systematic review of the literature.
METHODS
Computerized (PubMed, EMBASE, Cochrane Library) and manual searches were performed to identify human studies of all ages (patients) who received macrolides (intervention, with or without control) and documented SNHL (outcome). All study designs were assessed. Extracted data included macrolide regimen details, as well as the timing, severity, and reversibility of SNHL with drug cessation alone or with additional medical intervention. Study designs and the associated risk of bias were assessed.
RESULTS
The 44 publications (3 prospective, 41 retrospective) that met these criteria described 78 cases of audiometrically confirmed SNHL. SNHL was associated with oral and intravenous macrolide administration at standard and elevated doses. SNHL was irreversible in six cases, despite macrolide cessation (n = 5) and oral steroid treatment (n = 1). Irreversible SNHL was observed following 2 to 3 days of exposure. SNHL was reversible with macrolide cessation alone in 70 cases. In two cases, macrolide cessation coupled with oral steroid administration restored hearing. Reversible cases improved within hours to days. Nine studies also described 42 cases of subjective patient-reported hearing loss. Limitations in the data arose from study design, related comorbidities, and concomitant drug administration.
CONCLUSION
SNHL may follow macrolide exposure, even at standard oral doses. Further research is needed to understand the incidence, prevalence, and biological mechanism of its ototoxicity. Laryngoscope, 128:228-236, 2018.
Topics: Hearing Loss, Sensorineural; Humans; Macrolides; Risk Factors
PubMed: 28771738
DOI: 10.1002/lary.26799 -
Current Opinion in Microbiology Oct 2008In spite of decades of research, our knowledge of the mode of interaction of macrolide antibiotics with their ribosomal target and of the mechanism of action of these... (Review)
Review
In spite of decades of research, our knowledge of the mode of interaction of macrolide antibiotics with their ribosomal target and of the mechanism of action of these drugs remain fragmentary. Experimental facts obtained over the past several years question some of the concepts that were viewed as a 'common knowledge'. This review focuses on certain aspects of binding and action of macrolides that may need re-evaluation in view of the new findings.
Topics: Anti-Bacterial Agents; Bacteria; Macrolides; Models, Molecular; Molecular Structure; Protein Biosynthesis; Ribosomes
PubMed: 18804176
DOI: 10.1016/j.mib.2008.08.003 -
British Journal of Pharmacology Sep 2017Macrolides represent a large family of protein synthesis inhibitors of great clinical interest due to their applicability to human medicine. Macrolides are composed of a... (Review)
Review
Macrolides represent a large family of protein synthesis inhibitors of great clinical interest due to their applicability to human medicine. Macrolides are composed of a macrocyclic lactone of different ring sizes, to which one or more deoxy-sugar or amino sugar residues are attached. Macrolides act as antibiotics by binding to bacterial 50S ribosomal subunit and interfering with protein synthesis. The high affinity of macrolides for bacterial ribosomes, together with the highly conserved structure of ribosomes across virtually all of the bacterial species, is consistent with their broad-spectrum activity. Since the discovery of the progenitor macrolide, erythromycin, in 1950, many derivatives have been synthesised, leading to compounds with better bioavailability and acid stability and improved pharmacokinetics. These efforts led to the second generation of macrolides, including well-known members such as azithromycin and clarithromycin. Subsequently, in order to address increasing antibiotic resistance, a third generation of macrolides displaying improved activity against many macrolide resistant strains was developed. However, these improvements were accompanied with serious side effects, leading to disappointment and causing many researchers to stop working on macrolide derivatives, assuming that this procedure had reached the end. In contrast, a recent published breakthrough introduced a new chemical platform for synthesis and discovery of a wide range of diverse macrolide antibiotics. This chemical synthesis revolution, in combination with reduction in the side effects, namely, 'Ketek effects', has led to a macrolide renaissance, increasing the hope for novel and safe therapeutic agents to combat serious human infectious diseases.
Topics: Anti-Bacterial Agents; Bacteria; Communicable Diseases; Humans; Macrolides
PubMed: 28664582
DOI: 10.1111/bph.13936 -
The Cochrane Database of Systematic... Mar 2018Bronchiectasis is a chronic respiratory disease characterised by abnormal and irreversible dilatation and distortion of the smaller airways. Bacterial colonisation of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Bronchiectasis is a chronic respiratory disease characterised by abnormal and irreversible dilatation and distortion of the smaller airways. Bacterial colonisation of the damaged airways leads to chronic cough and sputum production, often with breathlessness and further structural damage to the airways. Long-term macrolide antibiotic therapy may suppress bacterial infection and reduce inflammation, leading to fewer exacerbations, fewer symptoms, improved lung function, and improved quality of life. Further evidence is required on the efficacy of macrolides in terms of specific bacterial eradication and the extent of antibiotic resistance.
OBJECTIVES
To determine the impact of macrolide antibiotics in the treatment of adults and children with bronchiectasis.
SEARCH METHODS
We identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted all searches on 18 January 2018.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) of at least four weeks' duration that compared macrolide antibiotics with placebo or no intervention for the long-term management of stable bronchiectasis in adults or children with a diagnosis of bronchiectasis by bronchography, plain film chest radiograph, or high-resolution computed tomography. We excluded studies in which participants had received continuous or high-dose antibiotics immediately before enrolment or before a diagnosis of cystic fibrosis, sarcoidosis, or allergic bronchopulmonary aspergillosis. Our primary outcomes were exacerbation, hospitalisation, and serious adverse events.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the titles and abstracts of 103 records. We independently screened the full text of 40 study reports and included 15 trials from 30 reports. Two review authors independently extracted outcome data and assessed risk of bias for each study. We analysed dichotomous data as odds ratios (ORs) and continuous data as mean differences (MDs) or standardised mean differences (SMDs). We used standard methodological procedures as expected by Cochrane.
MAIN RESULTS
We included 14 parallel-group RCTs and one cross-over RCT with interventions lasting from 8 weeks to 24 months. Of 11 adult studies with 690 participants, six used azithromycin, four roxithromycin, and one erythromycin. Four studies with 190 children used either azithromycin, clarithromycin, erythromycin, or roxithromycin.We included nine adult studies in our comparison between macrolides and placebo and two in our comparison with no intervention. We included one study with children in our comparison between macrolides and placebo and one in our comparison with no intervention.In adults, macrolides reduced exacerbation frequency to a greater extent than placebo (OR 0.34, 95% confidence interval (CI) 0.22 to 0.54; 341 participants; three studies; I = 65%; moderate-quality evidence). This translates to a number needed to treat for an additional beneficial outcome of 4 (95% CI 3 to 8). Data show no differences in exacerbation frequency between use of macrolides (OR 0.31, 95% CI 0.08 to 1.15; 43 participants; one study; moderate-quality evidence) and no intervention. Macrolides were also associated with a significantly better quality of life compared with placebo (MD -8.90, 95% CI -13.13 to -4.67; 68 participants; one study; moderate-quality evidence). We found no evidence of a reduction in hospitalisations (OR 0.56, 95% CI 0.19 to 1.62; 151 participants; two studies; I = 0%; low-quality evidence), in the number of participants with serious adverse events, including pneumonia, respiratory and non-respiratory infections, haemoptysis, and gastroenteritis (OR 0.49, 95% CI 0.20 to 1.23; 326 participants; three studies; I = 0%; low-quality evidence), or in the number experiencing adverse events (OR 0.83, 95% CI 0.51 to 1.35; 435 participants; five studies; I = 28%) in adults with macrolides compared with placebo.In children, there were no differences in exacerbation frequency (OR 0.40, 95% CI 0.11 to 1.41; 89 children; one study; low-quality evidence); hospitalisations (OR 0.28, 95% CI 0.07 to 1.11; 89 children; one study; low-quality evidence), serious adverse events, defined within the study as exacerbations of bronchiectasis or investigations related to bronchiectasis (OR 0.43, 95% CI 0.17 to 1.05; 89 children; one study; low-quality evidence), or adverse events (OR 0.78, 95% CI 0.33 to 1.83; 89 children; one study), in those receiving macrolides compared to placebo. The same study reported an increase in macrolide-resistant bacteria (OR 7.13, 95% CI 2.13 to 23.79; 89 children; one study), an increase in resistance to Streptococcus pneumoniae (OR 13.20, 95% CI 1.61 to 108.19; 89 children; one study), and an increase in resistance to Staphylococcus aureus (OR 4.16, 95% CI 1.06 to 16.32; 89 children; one study) with macrolides compared with placebo. Quality of life was not reported in the studies with children.
AUTHORS' CONCLUSIONS
Long-term macrolide therapy may reduce the frequency of exacerbations and improve quality of life, although supporting evidence is derived mainly from studies of azithromycin, rather than other macrolides, and predominantly among adults rather than children. However, macrolides should be used with caution, as limited data indicate an associated increase in microbial resistance. Macrolides are associated with increased risk of cardiovascular death and other serious adverse events in other populations, and available data cannot exclude a similar risk among patients with bronchiectasis.
Topics: Adult; Anti-Bacterial Agents; Azithromycin; Bronchiectasis; Child, Preschool; Clarithromycin; Erythromycin; Humans; Macrolides; Randomized Controlled Trials as Topic; Roxithromycin
PubMed: 29543980
DOI: 10.1002/14651858.CD012406.pub2 -
Advanced Drug Delivery Reviews May 2022Drug carriers to deliver macrolide antibiotics, such as azithromycin, show promise as antibacterial agents. Macrolide drug carriers have largely focused on improving the... (Review)
Review
Drug carriers to deliver macrolide antibiotics, such as azithromycin, show promise as antibacterial agents. Macrolide drug carriers have largely focused on improving the drug stability and pharmacokinetics, while reducing adverse reactions and improving antibacterial activity. Recently, macrolides have shown promise in treating inflammatory conditions by promoting a reparative effect and limiting detrimental pro-inflammatory responses, which shifts the immunologic setpoint from suppression to balance. While macrolide drug carriers have only recently been investigated for their ability to modulate immune responses, the previous strategies that deliver macrolides for antibacterial therapy provide a roadmap for repurposing the macrolide drug carriers for therapeutic interventions targeting inflammatory conditions. This review describes the antibacterial and immunomodulatory activity of macrolides, while assessing the past in vivo evaluation of drug carriers used to deliver macrolides with the intention of presenting a case for increased effort to translate macrolide drug carriers into the clinic.
Topics: Anti-Bacterial Agents; Azithromycin; Drug Carriers; Humans; Macrolides
PubMed: 35367307
DOI: 10.1016/j.addr.2022.114252 -
European Journal of Dermatology : EJD 1999Macrolide immunosuppressants are a new class of compounds sharing a macrolide-like structure and potent immunosuppressive activity in vitro and in vivo. Tacrolimus, the... (Review)
Review
Macrolide immunosuppressants are a new class of compounds sharing a macrolide-like structure and potent immunosuppressive activity in vitro and in vivo. Tacrolimus, the best known substance of this group, is registered in many countries for the prevention of transplant rejection. Numerous new substances of this group are in the pipelines of the pharmaceutical industries. Macrolide immunosuppressants are also effective in dermatological disorders. Due to their chemical structure these compounds can be used for topical treatment. Clinical studies have already shown highly effective topical therapy of atopic dermatitis with tacrolimus and the ascomycin derivative SDZ ASM 981, another macrolide immunosuppressant. In this article the pharmacological aspects of macrolide immunosuppressants, their supposed mechanisms of action, pre-clinical and clinical experience are reviewed.
Topics: Cyclosporine; Dermatologic Agents; Humans; Immunosuppressive Agents; Macrolides; Skin Diseases; Tacrolimus
PubMed: 10417434
DOI: No ID Found -
International Journal of Antimicrobial... Mar 2018The 16-membered macrolide antibiotics (e.g. tylosin A and josamycin) are mainly used in veterinary medicine, and are much less studied than their 14- and 15-membered... (Review)
Review
The 16-membered macrolide antibiotics (e.g. tylosin A and josamycin) are mainly used in veterinary medicine, and are much less studied than their 14- and 15-membered erythromycin-based cousins. Although these antibiotics have similar antibacterial profiles, with activity primarily against Gram-positive and a limited range of Gram-negative organisms, the 16-membered macrolides show some advantages. These include better gastrointestinal tolerance, lack of drug-drug interactions, and activity against certain resistant bacterial strains by extension of the peptide tunnel reach allowing additional interactions. In addition to antibacterial activity, the most famous representative of the class, tylosin A, as well as some derivatives of desmycosin (tylosin B), have shown antimalarial activity. Such activity has also been observed in the 14-membered macrolide antibiotics, azithromycin, solithromycin and clindamycin. This antimalarial activity provides the opportunity to investigate these drugs as cheap and effective antimalarials. This is an overview of the latest research on biosynthesis, structure, chemical properties and mode of action of 16-membered macrolides, with special emphasis on their most explored members: tylosin A and josamycin.
Topics: Animals; Anti-Bacterial Agents; Antimalarials; Gram-Positive Bacteria; Humans; Macrolides; Plasmodium
PubMed: 28668674
DOI: 10.1016/j.ijantimicag.2017.05.020 -
Current Topics in Medicinal Chemistry 2017Macrolides, polyketide natural products, and their 15-membered semi-synthetic derivatives are composed of substituted macrocyclic lactone ring and used primarily as... (Review)
Review
Macrolides, polyketide natural products, and their 15-membered semi-synthetic derivatives are composed of substituted macrocyclic lactone ring and used primarily as potent antibiotics. Recently their usefulness was extended to antimalarial and anti-inflammatory area. Hybrid macrolides presented in this article are the next generation semi-synthetic compounds that combine pharmacophores from antibacterial, antimalarial and anti-inflammatory area with 14- and 15-membered azalide scaffolds. Antibacterial azalide hybrids with sulphonamides showed improved activity against resistant streptococci while quinolone conjugates demonstrated full coverage of respiratory pathogens including macrolide resistant strains and their efficacy was confirmed in mouse pneumonia model. Antimalarial macrolide hybrids, mainly involving (chloro)quinoline pharmacophores, showed outstanding activity against chloroquine resistant strains, favourable pharmacokinetics, promising in vivo efficacy as well as encouraging developmental potential. Anti-inflammatory hybrids were obtained by combining macrolides with corticosteroid and non-steroidal anti-inflammatory drugs. They were found active in in vivo animal models of locally induced inflammation, asthma, inflammatory bowel disease and rheumatoid arthritis and demonstrated improved safety over parent steroid drugs. Overall, macrolide hybrids possess significant potential to be developed as potent novel medicines in therapeutic areas of utmost pharmaceutical interest.
Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antimalarials; Bacteria; Drug Discovery; Humans; Inflammation; Macrolides; Malaria
PubMed: 27697049
DOI: 10.2174/1568026616666160927160036 -
Chemistry (Weinheim An Der Bergstrasse,... Mar 2020The nargenicin family of antibiotic macrolides comprise a group of bacterial natural products with a rare ether bridged cis-decalin moiety and a narrow spectrum of... (Review)
Review
The nargenicin family of antibiotic macrolides comprise a group of bacterial natural products with a rare ether bridged cis-decalin moiety and a narrow spectrum of activity. Most family members were identified almost four decades ago and were placed on the shelf due to the numbers of broad-spectrum compounds available at the time. However, in light of rising rates of antimicrobial resistance, there has been a renewed interest in the use of narrow-spectrum antimicrobials. Here, we review the history of this family of compounds, including synthetic approaches, and highlight the recently uncovered genetic basis for nargenicin production. Given the renewed pharmaceutical interest in these compounds, we also investigate structure-activity relationships among these molecules, with a view to the future development of members of this unusual antibiotic family.
Topics: Anti-Bacterial Agents; Bridged-Ring Compounds; Humans; Lactones; Macrolides; Naphthalenes; Structure-Activity Relationship
PubMed: 31667915
DOI: 10.1002/chem.201904053