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Journal of the American Chemical Society Sep 2020Lankacidins are a class of polyketide natural products isolated from that show promising antimicrobial activity. Owing to their complex molecular architectures and...
Lankacidins are a class of polyketide natural products isolated from that show promising antimicrobial activity. Owing to their complex molecular architectures and chemical instability, structural assignment and derivatization of lankacidins are challenging tasks. Herein we describe three fully synthetic approaches to lankacidins that enable access to new structural variability within the class. We use these routes to systematically generate stereochemical derivatives of both cyclic and acyclic lankacidins. Additionally, we access a new series of lankacidins bearing a methyl group at the C4 position, a modification intended to increase chemical stability. In the course of this work, we discovered that the reported structures for two natural products of the lankacidin class were incorrect, and we determine the correct structures of 2,18--lankacidinol B and -lankacidinol. We also evaluate the ability of several - and -lankacidins to inhibit the growth of bacteria and to inhibit translation in vitro. This work grants insight into the rich chemical complexity of this class of antibiotics and provides an avenue for further structural derivatization.
Topics: Anti-Bacterial Agents; Bacillus subtilis; Crystallography, X-Ray; Macrolides; Microbial Sensitivity Tests; Micrococcus; Models, Molecular; Molecular Structure; Staphylococcus aureus; Stereoisomerism; Streptomyces
PubMed: 32786797
DOI: 10.1021/jacs.0c06648 -
The Cochrane Database of Systematic... Sep 2018Scrub typhus, an important cause of acute fever in Asia, is caused by Orientia tsutsugamushi, an obligate intracellular bacterium. Antibiotics currently used to treat... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Scrub typhus, an important cause of acute fever in Asia, is caused by Orientia tsutsugamushi, an obligate intracellular bacterium. Antibiotics currently used to treat scrub typhus include tetracyclines, chloramphenicol, macrolides, and rifampicin.
OBJECTIVES
To assess and compare the effects of different antibiotic regimens for treatment of scrub typhus.
SEARCH METHODS
We searched the following databases up to 8 January 2018: the Cochrane Infectious Diseases Group specialized trials register; CENTRAL, in the Cochrane Library (2018, Issue 1); MEDLINE; Embase; LILACS; and the metaRegister of Controlled Trials (mRCT). We checked references and contacted study authors for additional data. We applied no language or date restrictions.
SELECTION CRITERIA
Randomized controlled trials (RCTs) or quasi-RCTs comparing antibiotic regimens in people with the diagnosis of scrub typhus based on clinical symptoms and compatible laboratory tests (excluding the Weil-Felix test).
DATA COLLECTION AND ANALYSIS
For this update, two review authors re-extracted all data and assessed the certainty of evidence. We meta-analysed data to calculate risk ratios (RRs) for dichotomous outcomes when appropriate, and elsewhere tabulated data to facilitate narrative analysis.
MAIN RESULTS
We included six RCTs and one quasi-RCT with 548 participants; they took place in the Asia-Pacific region: Korea (three trials), Malaysia (one trial), and Thailand (three trials). Only one trial included children younger than 15 years (N = 57). We judged five trials to be at high risk of performance and detection bias owing to inadequate blinding. Trials were heterogenous in terms of dosing of interventions and outcome measures. Across trials, treatment failure rates were low.Two trials compared doxycycline to tetracycline. For treatment failure, the difference between doxycycline and tetracycline is uncertain (very low-certainty evidence). Doxycycline compared to tetracycline may make little or no difference in resolution of fever within 48 hours (risk ratio (RR) 1.14, 95% confidence interval (CI) 0.90 to 1.44, 55 participants; one trial; low-certainty evidence) and in time to defervescence (116 participants; one trial; low-certainty evidence). We were unable to extract data for other outcomes.Three trials compared doxycycline versus macrolides. For most outcomes, including treatment failure, resolution of fever within 48 hours, time to defervescence, and serious adverse events, we are uncertain whether study results show a difference between doxycycline and macrolides (very low-certainty evidence). Macrolides compared to doxycycline may make little or no difference in the proportion of patients with resolution of fever within five days (RR 1.05, 95% CI 0.99 to 1.10; 185 participants; two trials; low-certainty evidence). Another trial compared azithromycin versus doxycycline or chloramphenicol in children, but we were not able to disaggregate date for the doxycycline/chloramphenicol group.One trial compared doxycycline versus rifampicin. For all outcomes, we are uncertain whether study results show a difference between doxycycline and rifampicin (very low-certainty evidence). Of note, this trial deviated from the protocol after three out of eight patients who had received doxycycline and rifampicin combination therapy experienced treatment failure.Across trials, mild gastrointestinal side effects appeared to be more common with doxycycline than with comparator drugs.
AUTHORS' CONCLUSIONS
Tetracycline, doxycycline, azithromycin, and rifampicin are effective treatment options for scrub typhus and have resulted in few treatment failures. Chloramphenicol also remains a treatment option, but we could not include this among direct comparisons in this review.Most available evidence is of low or very low certainty. For specific outcomes, some low-certainty evidence suggests there may be little or no difference between tetracycline, doxycycline, and azithromycin as treatment options. Given very low-certainty evidence for rifampicin and the risk of inducing resistance in undiagnosed tuberculosis, clinicians should not regard this as a first-line treatment option. Clinicians could consider rifampicin as a second-line treatment option after exclusion of active tuberculosis.Further research should consist of additional adequately powered trials of doxycycline versus azithromycin or other macrolides, trials of other candidate antibiotics including rifampicin, and trials of treatments for severe scrub typhus. Researchers should standardize diagnostic techniques and reporting of clinical outcomes to allow robust comparisons.
Topics: Adult; Anti-Bacterial Agents; Azithromycin; Child, Preschool; Chloramphenicol; Doxycycline; Humans; Macrolides; Randomized Controlled Trials as Topic; Rifampin; Scrub Typhus; Tetracycline
PubMed: 30246875
DOI: 10.1002/14651858.CD002150.pub2 -
Emerging Infectious Diseases Oct 2020Macrolide-resistant Bordetella pertussis emerged in Vietnam during 2016-2017. Direct analyses of swab samples from 10 patients with pertussis revealed a...
Macrolide-resistant Bordetella pertussis emerged in Vietnam during 2016-2017. Direct analyses of swab samples from 10 patients with pertussis revealed a macrolide-resistant mutation, A2047G, in the 23S rRNA. We identified the MT104 genotype of macrolide-resistant B. pertussis (which is prevalent in mainland China) and its variants in these patients.
Topics: Anti-Bacterial Agents; Bordetella pertussis; China; Drug Resistance, Bacterial; Erythromycin; Humans; Macrolides; RNA, Ribosomal, 23S; Vietnam
PubMed: 32946738
DOI: 10.3201/eid2610.201035 -
Proceedings of the National Academy of... Dec 2022Although lacking an adaptive immune system and often living in habitats with dense and diverse bacterial populations, marine invertebrates thrive in the presence of...
Although lacking an adaptive immune system and often living in habitats with dense and diverse bacterial populations, marine invertebrates thrive in the presence of potentially challenging microbial pathogens. However, the mechanisms underlying this resistance remain largely unexplored and promise to reveal novel strategies of microbial resistance. Here, we provide evidence that a mud-dwelling clam, s, synthesizes, stores, and secretes the antibiotic erythromycin. Liquid chromatography coupled with mass spectrometry, immunocytochemistry, fluorescence in situ hybridization, RNA interference, and enzyme-linked immunosorbent assay revealed that this potent macrolide antimicrobial, thought to be synthesized only by microorganisms, is produced by specific mucus-rich cells beneath the clam's mantle epithelium, which interfaces directly with the bacteria-rich environment. The antibacterial activity was confirmed by bacteriostatic assay. Genetic, ontogenetic, phylogenetic and genomic evidence, including genotypic segregation ratios in a family of full siblings, gene expression in clam larvae, phylogenetic tree, and synteny conservation in the related genome region further revealed that the genes responsible for erythromycin production are of animal origin. The detection of this antibiotic in another clam species showed that the production of this macrolide is not exclusive to and may be a common strategy among marine invertebrates. The finding of erythromycin production by a marine invertebrate offers a striking example of convergent evolution in secondary metabolite synthesis between the animal and bacterial domains. These findings open the possibility of engineering-animal tissues for the localized production of an antibacterial secondary metabolite.
Topics: Animals; Erythromycin; Phylogeny; In Situ Hybridization, Fluorescence; Bivalvia; Anti-Bacterial Agents; Macrolides
PubMed: 36442100
DOI: 10.1073/pnas.2214150119 -
Journal of the Pediatric Infectious... Feb 2018Pneumonia, most often caused by a respiratory virus, is common in childhood. Mycoplasma pneumoniae also is detected frequently, particularly in older children in the era... (Review)
Review
Pneumonia, most often caused by a respiratory virus, is common in childhood. Mycoplasma pneumoniae also is detected frequently, particularly in older children in the era of pneumococcal conjugate vaccination. Despite recommendations for β-lactam antibiotics, macrolide antibiotics, including erythromycin, clarithromycin, and azithromycin, are prescribed frequently to children with acute lower respiratory infection. However, the significance of detecting "atypical" pathogens, including M pneumoniae, in children remains contentious. Considering the potential for antibacterial and anti-inflammatory activities of macrolides, our understanding of the role of these drugs in acute and chronic infections and in inflammatory conditions is changing. Some observational data have revealed improved outcomes in adults and children with pneumonia who are prescribed macrolides, although its widespread use has led to increases in macrolide resistance in Streptococcus pneumoniae and M pneumoniae. Clinical trials to define the role of macrolides in pediatric acute respiratory infection must be prioritized.
Topics: Anti-Bacterial Agents; Child; Community-Acquired Infections; Humans; Macrolides; Pneumonia, Bacterial; Treatment Outcome
PubMed: 29096010
DOI: 10.1093/jpids/pix083 -
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 -
Ecotoxicology and Environmental Safety Jun 2023The ecological effects of antibiotics in surface water have attracted increasing research attention. In this study, we investigated the combined ecotoxicity of...
The ecological effects of antibiotics in surface water have attracted increasing research attention. In this study, we investigated the combined ecotoxicity of erythromycin (ERY) and roxithromycin (ROX) on the microalgae, Chlorella pyrenoidosa, and the removal of ERY and ROX during the exposure. The calculated 96-h median effect concentration (EC) values of ERY, ROX, and their mixture (2:1 w/w) were 7.37, 3.54, and 7.91 mg∙L, respectively. However, the predicted EC values of ERY+ROX mixture were 5.42 and 1.51 mg∙L, based on the concentration addition and independent action models, respectively. This demonstrated the combined toxicity of ERY+ ROX mixture showed an antagonistic effect on Chlorella pyrenoidosa. During the 14-d culture, low-concentration (EC) treatments with ERY, ROX, and their mixture caused the growth inhibition rate to decrease during the first 12 d and increase slightly at 14 d. In contrast, high-concentration (EC) treatments significantly inhibited microalgae growth (p < 0.05). Changes in the total chlorophyll contents, SOD and CAT activities, and MDA contents of microalgae suggested that individual treatments with ERY and ROX induced higher oxidative stress than combined treatments. After the 14-d culture time, residual Ery in low and high concentration Ery treatments were 17.75% and 74.43%, and the residual Rox were 76.54% and 87.99%, but the residuals were 8.03% and 73.53% in ERY+ ROX combined treatment. These indicated that antibiotic removal efficiency was higher in combined treatments than that in individual treatments, especially at low concentrations (EC). Correlation analysis suggested that there was a significant negative correlation between the antibiotic removal efficiency of C. pyrenoidosa and their SOD activity and MDA content, and the enhanced antibiotic removal ability of microalgae benefited from increased cell growth and chlorophyll content. Findings in this study contribute to predicting ecological risk of coexisting antibiotics in aquatic environment, and to improving biological treatment technology of antibiotics in wastewater.
Topics: Roxithromycin; Erythromycin; Chlorella; Anti-Bacterial Agents; Chlorophyll; Superoxide Dismutase; Microalgae; Water Pollutants, Chemical
PubMed: 37084660
DOI: 10.1016/j.ecoenv.2023.114929 -
European Respiratory Review : An... Dec 2017In the present review we provide currently available evidence for the use of macrolides in the treatment of diffuse interstitial lung diseases (ILDs). Up to now,... (Review)
Review
In the present review we provide currently available evidence for the use of macrolides in the treatment of diffuse interstitial lung diseases (ILDs). Up to now, research on macrolides has mainly focused on three areas. First, macrolides have shown some promising results in cellular models and case reports as antifibrotic agents, by promoting autophagy and clearance of intracellular protein aggregates and acting as regulators of surfactant homeostasis. Secondly, macrolides have an immunomodulatory effect, which has been applied in some organising pneumonia cases. In particular, macrolides have been tested in association with systemic corticosteroids as steroid-sparing agents and alone as either first-line agents in mild cases or second-line agents where steroids were poorly tolerated or had failed. Thirdly, a recent area of research concerns the possible role of macrolides as modulators of lung microbiota and the host-microbiota interaction. This function has been particularly studied in idiopathic pulmonary fibrosis patients, in whom changes in microbiota have been proved to be associated with disease progression. However, the lack of high-quality studies makes the application of macrolide therapy in ILDs a field in which research should be conducted on a large scale.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Drug Administration Schedule; Host-Pathogen Interactions; Humans; Lung; Lung Diseases, Interstitial; Macrolides; Time Factors; Treatment Outcome
PubMed: 29212838
DOI: 10.1183/16000617.0082-2017 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Sep 2021Macrolide antibiotics are a class of broad-spectrum antibiotics with the macrolide as core nucleus. Recently, antibiotic pollution has become an important environmental... (Review)
Review
Macrolide antibiotics are a class of broad-spectrum antibiotics with the macrolide as core nucleus. Recently, antibiotic pollution has become an important environmental problem due to the irregular production and abuse of macrolide antibiotics. Microbial degradation is one of the most effective methods to deal with antibiotic pollution. This review summarizes the current status of environmental pollution caused by macrolide antibiotics, the degradation strains, the degradation enzymes, the degradation pathways and the microbial processes for degrading macrolide antibiotics. Moreover, the critical challenges on the biodegradation of macrolide antibiotics were also discussed.
Topics: Anti-Bacterial Agents; Biodegradation, Environmental; Macrolides
PubMed: 34622622
DOI: 10.13345/j.cjb.200714 -
Nature Communications Jul 2021Macrolides and ketolides comprise a family of clinically important antibiotics that inhibit protein synthesis by binding within the exit tunnel of the bacterial...
Macrolides and ketolides comprise a family of clinically important antibiotics that inhibit protein synthesis by binding within the exit tunnel of the bacterial ribosome. While these antibiotics are known to interrupt translation at specific sequence motifs, with ketolides predominantly stalling at Arg/Lys-X-Arg/Lys motifs and macrolides displaying a broader specificity, a structural basis for their context-specific action has been lacking. Here, we present structures of ribosomes arrested during the synthesis of an Arg-Leu-Arg sequence by the macrolide erythromycin (ERY) and the ketolide telithromycin (TEL). Together with deep mutagenesis and molecular dynamics simulations, the structures reveal how ERY and TEL interplay with the Arg-Leu-Arg motif to induce translational arrest and illuminate the basis for the less stringent sequence-specific action of ERY over TEL. Because programmed stalling at the Arg/Lys-X-Arg/Lys motifs is used to activate expression of antibiotic resistance genes, our study also provides important insights for future development of improved macrolide antibiotics.
Topics: Amino Acid Motifs; Amino Acid Sequence; Anti-Bacterial Agents; Bacillus subtilis; Binding Sites; Cryoelectron Microscopy; Drug Resistance, Microbial; Erythromycin; Genes, Bacterial; Ketolides; Macrolides; Methyltransferases; Molecular Dynamics Simulation; Mutagenesis, Insertional; Protein Biosynthesis; Protein Synthesis Inhibitors; Ribosomes
PubMed: 34294725
DOI: 10.1038/s41467-021-24674-9