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The Journal of Antibiotics May 2017Erythromycin and its analogs are used to treat respiratory tract and other infections. The broad use of these antibiotics during the last 5 decades has led to resistance... (Review)
Review
Erythromycin and its analogs are used to treat respiratory tract and other infections. The broad use of these antibiotics during the last 5 decades has led to resistance that can range from 20% to over 70% in certain parts of the world. Efforts to find macrolides that were active against macrolide-resistant strains led to the development of erythromycin analogs with alkyl-aryl side chains that mimicked the sugar side chain of 16-membered macrolides, such as tylosin. Further modifications were made to improve the potency of these molecules by removal of the cladinose sugar to obtain a smaller molecule, a modification that was learned from an older macrolide, pikromycin. A keto group was introduced after removal of the cladinose sugar to make the new ketolide subclass. Only one ketolide, telithromycin, received marketing authorization but because of severe adverse events, it is no longer widely used. Failure to identify the structure-relationship responsible for this clinical toxicity led to discontinuation of many ketolides that were in development. One that did complete clinical development, cethromycin, did not meet clinical efficacy criteria and therefore did not receive marketing approval. Work on developing new macrolides was re-initiated after showing that inhibition of nicotinic acetylcholine receptors by the imidazolyl-pyridine moiety on the side chain of telithromycin was likely responsible for the severe adverse events. Solithromycin is a fourth-generation macrolide that has a fluorine at the 2-position, and an alkyl-aryl side chain that is different from telithromycin. Solithromycin interacts at three sites on the bacterial ribosome, has activity against strains resistant to older macrolides (including telithromycin), and is mostly bactericidal. Pharmaceutical scientists involved in the development of macrolide antibiotics have learned from the teachings of Professor Satoshi Omura and progress in this field was not possible without his endeavors.
Topics: Anti-Bacterial Agents; Bacteria; Bacterial Infections; Drug Design; Drug Resistance, Bacterial; Humans; Macrolides; Structure-Activity Relationship
PubMed: 27899792
DOI: 10.1038/ja.2016.137 -
Annals of Clinical Microbiology and... May 2021Drug repurposing otherwise known as drug repositioning or drug re-profiling is a time-tested approach in drug discovery through which new medical uses are being... (Review)
Review
BACKGROUND
Drug repurposing otherwise known as drug repositioning or drug re-profiling is a time-tested approach in drug discovery through which new medical uses are being established for already known drugs. Antibiotics are among the pharmacological agents being investigated for potential anti-SARS-COV-2 activities. The antibiotics are used either to resolve bacterial infections co-existing with COVID-19 infections or exploitation of their potential antiviral activities. Herein, we aimed to review the various antibiotics that have been repositioned for the management of COVID-19.
METHODS
This literature review was conducted from a methodical search on PubMed and Web of Science regarding antibiotics used in patients with COVID-19 up to July 5, 2020.
RESULTS
Macrolide and specifically azithromycin is the most common antibiotic used in the clinical management of COVID-19. The other antibiotics used in COVID-19 includes teicoplanin, clarithromycin, doxycycline, tetracyclines, levofloxacin, moxifloxacin, ciprofloxacin, and cefuroxime. In patients with COVID-19, antibiotics are used for their immune-modulating, anti-inflammatory, and antiviral properties. The precise antiviral mechanism of most of these antibiotics has not been determined. Moreover, the use of some of these antibiotics against SARS-CoV-2 infection remains highly controversial and not widely accepted.
CONCLUSION
The heavy use of antibiotics during the COVID-19 pandemic would likely worsen antibiotic resistance crisis. Consequently, antibiotic stewardship should be strengthened in order to prevent the impacts of COVID-19 on the antibiotic resistance crisis.
Topics: Aminoglycosides; Anti-Bacterial Agents; Drug Repositioning; Fluoroquinolones; Glycopeptides; Humans; Macrolides; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34020659
DOI: 10.1186/s12941-021-00444-9 -
Applied and Environmental Microbiology Apr 2020Conjugation is one of the main mechanisms involved in the spread and maintenance of antibiotic resistance in bacterial populations. We recently showed that the emerging...
Conjugation is one of the main mechanisms involved in the spread and maintenance of antibiotic resistance in bacterial populations. We recently showed that the emerging macrolide resistance in the soilborne equine and zoonotic pathogen is conferred by the (46) gene carried on the 87-kb conjugative plasmid pRErm46. Here, we investigated the conjugal transferability of pRErm46 to 14 representative bacteria likely encountered by in the environmental habitat. mating experiments demonstrated conjugation to different members of the genus as well as to and spp. at frequencies ranging from ∼10 to 10 pRErm46 transfer was also observed in mating experiments in soil and horse manure, albeit at a low frequency and after prolonged incubation at 22 to 30°C (environmental temperatures), not 37°C. All transconjugants were able to transfer pRErm46 back to Conjugation could not be detected with or spp. or several members of the more distant phylum such as , , or Thus, the pRErm46 host range appears to span several actinobacterial orders with certain host restriction within the All bacterial species that acquired pRErm46 expressed increased macrolide resistance with no significant deleterious impact on fitness, except in the case of Our results indicate that actinobacterial members of the environmental microbiota can both acquire and transmit the pRErm46 plasmid and thus potentially contribute to the maintenance and spread of (46)-mediated macrolide resistance in equine farms. This study demonstrates the efficient horizontal transfer of the conjugative plasmid pRErm46, recently identified as the cause of the emerging macrolide resistance among equine isolates of this pathogen, to and from different environmental , including a variety of rhodococci as well as and spp. The reported data support the notion that environmental microbiotas may act as reservoirs for the endemic maintenance of antimicrobial resistance in an antibiotic pressurized farm habitat.
Topics: Actinobacteria; Anti-Bacterial Agents; Drug Resistance, Bacterial; Gene Transfer, Horizontal; Genes, Bacterial; Macrolides; Plasmids; Rhodococcus equi
PubMed: 32169935
DOI: 10.1128/AEM.00108-20 -
Polskie Archiwum Medycyny Wewnetrznej 2012Acute exacerbations are a major contributor to health care costs and a leading cause of death in patients with chronic obstructive pulmonary disease (COPD). A reduction... (Review)
Review
Acute exacerbations are a major contributor to health care costs and a leading cause of death in patients with chronic obstructive pulmonary disease (COPD). A reduction in acute exacerbations of COPD (AECOPD) would lead to significant improvements in patient well-being and survival. Bacterial and viral infections cause a majority of AECOPD episodes; however, with the exception of influenza and pneumococcal vaccines, preventative therapies for exacerbations do not directly address these infectious causes of AECOPD. Antibiotics were shown to have marginal benefit in preventing AECOPD several decades ago; however, since then, pathogens and antibiotics have changed substantially. Macrolides display immunomodulatory and anti-inflammatory effects in addition to their direct antibacterial effect. Several studies have examined macrolides in AECOPD prevention, with a recent landmark study by Albert et al. clearly demonstrating the efficacy of azithromycin in preventing AECOPD. Unfortunately, the rate of isolation of macrolide-resistant pathogens does increase with such treatment. Macrolides could also suppress bacterial colonization and thus decrease airway inflammation, thereby interrupting the vicious cycle of inflammation and infection in COPD. COPD patients with two or more exacerbations a year in spite of appropriate standard therapy are potential candidates for this therapeutic approach. However, optimal duration and dosing of macrolide prophylaxis for AECOPD remains uncertain.
Topics: Anti-Bacterial Agents; Azithromycin; Disease Progression; Humans; Macrolides; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index
PubMed: 22353707
DOI: No ID Found -
Emerging Infectious Diseases Jun 2021Emergence of macrolide-resistant Mycoplasma pneumoniae (MRMp) challenges empiric macrolide therapy. Our goal was to determine MRMp rates and define characteristics of...
Emergence of macrolide-resistant Mycoplasma pneumoniae (MRMp) challenges empiric macrolide therapy. Our goal was to determine MRMp rates and define characteristics of children infected with macrolide-sensitive M. pneumoniae (MSMp) versus MRMp in Ohio, USA. We cultured PCR-positive M. pneumoniae specimens and sequenced M. pneumoniae-positive cultures to detect macrolide resistance mutations. We reviewed medical records to compare characteristics of both groups. We identified 14 (2.8%) MRMp and 485 (97.2%) MSMp samples. Patients in these groups had similar demographics and clinical characteristics, but patients with MRMp had longer hospitalizations, were more likely to have received previous macrolides, and were more likely to have switched to alternative antimicrobial drugs. MRMp-infected patients also had ≈5-fold greater odds of pediatric intensive care unit admission. Rates of MRMp infections in children in central Ohio are low, but clinicians should remain aware of the risk for severe illness caused by these pathogens.
Topics: Anti-Bacterial Agents; Child; Drug Resistance, Bacterial; Humans; Macrolides; Mycoplasma pneumoniae; Ohio; Pneumonia, Mycoplasma
PubMed: 34013867
DOI: 10.3201/eid2706.203206 -
The American Journal of Tropical... Nov 2023Azithromycin mass drug administration decreases child mortality but also selects for antibiotic resistance. Herein, we evaluate macrolide resistance of nasopharyngeal... (Randomized Controlled Trial)
Randomized Controlled Trial
Temporal Trends in Phenotypic Macrolide and Nonmacrolide Resistance for Streptococcus pneumoniae Nasopharyngeal Samples Up to 36 Months after Mass Azithromycin Administration in a Cluster-Randomized Trial in Niger.
Azithromycin mass drug administration decreases child mortality but also selects for antibiotic resistance. Herein, we evaluate macrolide resistance of nasopharyngeal Streptococcus pneumoniae after azithromycin MDA. In a cluster-randomized trial, children 1-59 months received azithromycin or placebo biannually. Fifteen villages from each arm were randomly selected for antimicrobial resistance testing, and 10-15 randomly selected swabs from enrolled children at each village were processed for S. pneumoniae isolation and resistance testing. The primary prespecified outcome was macrolide resistance fraction for azithromycin versus placebo villages at 36 months. Secondary non-prespecified outcomes were comparisons of azithromycin and placebo for: 1) macrolide resistance at 12, 24, and 36 months; 2) nonmacrolide resistance at 36 months; and 3) suspected-erm mutation. At 36 months, 423 swabs were obtained and 322 grew S. pneumoniae, (azithromycin: 146/202, placebo: 176/221). Mean resistance prevalence was non-significantly higher in treatment than placebo (mixed-effects model: 14.6% vs. 8.9%; OR = 2.0, 95% CI: 0.99-3.97). However, when all time points were evaluated, macrolide resistance prevalence was significantly higher in the azithromycin group (β = 0.102, 95% CI: 0.04-0.167). For all nonmacrolides, resistance prevalence at 36 months was not different between the two groups. Azithromycin and placebo were not different for suspected-erm mutation prevalence. Macrolide resistance was higher in the azithromycin group over all time points, but not at 36 months. Although this suggests resistance may not continue to increase after biannual MDA, more studies are needed to clarify when MDA can safely decrease mortality and morbidity in lower- and middle-income countries.
Topics: Child; Humans; Infant; Azithromycin; Anti-Bacterial Agents; Macrolides; Streptococcus pneumoniae; Mass Drug Administration; Niger; Drug Resistance, Bacterial
PubMed: 37783458
DOI: 10.4269/ajtmh.23-0431 -
Antimicrobial Agents and Chemotherapy Jul 2021Macrolide resistance is always a concern when treating Mycobacterium abscessus infections. MAB_2355c was identified previously as a possible new factor that confers the...
Macrolide resistance is always a concern when treating Mycobacterium abscessus infections. MAB_2355c was identified previously as a possible new factor that confers the intrinsic resistance of 194 clinical M. abscessus isolates to clarithromycin. Herein, the potential mechanism by which MAB_2355c exerts macrolide resistance was explored by bioinformatics analysis, cloning and protein purification, ATP hydrolysis assay, gene knockout and complementation, antibiotic sensitivity, and transcription-translation assays. MAB_2355c is a putative ATP-binding cassette F (ABC-F) family protein. Purified MAB_2355c protein exhibits ATP hydrolysis activity, which can be inhibited by ribosome-targeting antibiotics. mRNA expression is upregulated more significantly after exposure to macrolides than after exposure to other ribosome-targeting antibiotics. deleted strains showed increased sensitivity to macrolides, which was reduced by complementation. Finally, MAB_2355c rescued the transcription and translation activities affected by macrolides . These findings suggest that MAB_2355c confers the resistance of M. abscessus to macrolides by ribosome protection, thus complementing other known resistance mechanisms.
Topics: Anti-Bacterial Agents; Clarithromycin; Drug Resistance, Bacterial; Humans; Macrolides; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Ribosomes
PubMed: 34097497
DOI: 10.1128/AAC.00330-21 -
Nature Communications Jan 2018The production of antibiotics by microbes in the environment and their use in medicine and agriculture select for existing and emerging resistance. To address this...
The production of antibiotics by microbes in the environment and their use in medicine and agriculture select for existing and emerging resistance. To address this inevitability, prudent development of antibiotic drugs requires careful consideration of resistance evolution. Here, we identify the molecular basis for expanded substrate specificity in MphI, a macrolide kinase (Mph) that does not confer resistance to erythromycin, in contrast to other known Mphs. Using a combination of phylogenetics, drug-resistance phenotypes, and in vitro enzyme assays, we find that MphI and MphK phosphorylate erythromycin poorly resulting in an antibiotic-sensitive phenotype. Using likelihood reconstruction of ancestral sequences and site-saturation combinatorial mutagenesis, supported by Mph crystal structures, we determine that two non-obvious mutations in combination expand the substrate range. This approach should be applicable for studying the functional evolution of any antibiotic resistance enzyme and for evaluating the evolvability of resistance enzymes to new generations of antibiotic scaffolds.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Bacterial; Erythromycin; Escherichia coli; Macrolides; Models, Molecular; Molecular Structure; Phosphotransferases; Phylogeny; Protein Domains; Substrate Specificity
PubMed: 29317655
DOI: 10.1038/s41467-017-02680-0 -
Journal of Korean Medical Science Nov 2021Public interventions have shown to optimize the use of antibiotics in children with acute otitis media (AOM). In this study, we describe the AOM-related antibiotic use...
Public interventions have shown to optimize the use of antibiotics in children with acute otitis media (AOM). In this study, we describe the AOM-related antibiotic use among children in South Korea using national cohort data. We retrieved the Health Insurance Review & Assessment Service data to construct a national cohort of children aged 0-6 years who had been diagnosed with AOM between 2012 and 2018. Of 25,212,264 children included, the antibiotic prescription has increased for amoxicillin/amoxicillin-clavulanate from 56.1% in 2012 to 61.8% in 2018. Prescription has decreased for cephalosporin (35.1% in 2012 to 31.8% in 2018) and macrolide (8.7% in 2012 to 6.4% in 2018). National cohort data have shown an increased trend in AOM-related aminopenicillin prescription and downward trend cephalosporin and macrolide use in South Korea. A multi-faceted approach is required to control the antimicrobial resistance at a population level.
Topics: Amoxicillin; Anti-Bacterial Agents; Cephalosporins; Child; Child, Preschool; Female; Humans; Infant; Macrolides; Male; Otitis Media; Practice Patterns, Physicians'; Republic of Korea
PubMed: 34845876
DOI: 10.3346/jkms.2021.36.e317 -
Chronic Respiratory Disease 2005Macrolide antibiotics have been licensed since the 1950s and have an important role in the treatment of a diverse range of infectious diseases. Macrolide antibiotics... (Review)
Review
Macrolide antibiotics have been licensed since the 1950s and have an important role in the treatment of a diverse range of infectious diseases. Macrolide antibiotics have antibacterial activity against gram-positive bacteria, some gram-negative bacteria and intracellular pathogens. The spectrum of antibacterial activity combined with excellent intracellular and tissue penetration has led to the extensive use of this class of drugs in respiratory disease. Macrolide antibiotics also have demonstrated anti-inflammatory properties in various in vitro and in vivo model systems. Novel antimicrobial and anti-inflammatory properties of macrolide may result in clinical benefits, particularly in conditions where the infectious agent is inherently resistant to macrolides. Three randomized control trials have demonstrated improved lung function in patients treated with the macrolide antibiotic, azithromycin. Azithromycin was generally well tolerated and resulted in reduction in the inflammatory response which may be due to an immunomodulatory role. Short term studies (three to six months) have not demonstrated the development of increased bacterial resistance or the emergence of new pathogens following azithromycin.
Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Cystic Fibrosis; Humans; Macrolides
PubMed: 16279156
DOI: 10.1191/1479972305cd066rs