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Frontiers in Cellular and Infection... 2023is an important pathogen causing upper and lower respiratory tract infections in children and other age groups. Macrolides are the recommended treatments of choice for...
is an important pathogen causing upper and lower respiratory tract infections in children and other age groups. Macrolides are the recommended treatments of choice for infections. However, macrolide resistance in is increasing worldwide, which complicates the treatment strategies. The mechanisms of macrolide resistance have been extensively studied focusing on the mutations in and ribosomal proteins. Since the secondary treatment choice for pediatric patients is very limited, we decided to look for potential new treatment strategies in macrolide drugs and investigate possible new mechanisms of resistance. We performed an selection of mutants resistant to five macrolides (erythromycin, roxithromycin, azithromycin, josamycin, and midecamycin) by inducing the parent strain M129 with increasing concentrations of the drugs. The evolving cultures in every passage were tested for their antimicrobial susceptibilities to eight drugs and mutations known to be associated with macrolide resistance by PCR and sequencing. The final selected mutants were also analyzed by whole-genome sequencing. Results showed that roxithromycin is the drug that most easily induces resistance (at 0.25 mg/L, with two passages, 23 days), while with midecamycin it is most difficult (at 5.12 mg/L, with seven passages, 87 days). Point mutations C2617A/T, A2063G, or A2064C in domain V of were detected in mutants resistant to the 14- and 15-membered macrolides, while A2067G/C was selected for the 16-membered macrolides. Single amino acid changes (G72R, G72V) in ribosomal protein L4 emerged during the induction by midecamycin. Genome sequencing identified sequence variations in , , , , and in one of the () genes in the mutants. Mutants induced by the 14- or 15-membered macrolides were resistant to all macrolides, while those induced by the 16-membered macrolides (midecamycin and josamycin) remained susceptible to the 14- and 15-membered macrolides. In summary, these data demonstrated that midecamycin is less potent in inducing resistance than other macrolides, and the induced resistance is restrained to the 16-membered macrolides, suggesting a potential benefit of using midecamycin as a first treatment choice if the strain is susceptible.
Topics: Humans; Child; Anti-Bacterial Agents; Mycoplasma pneumoniae; Macrolides; Roxithromycin; Josamycin; RNA, Ribosomal, 23S; Microbial Sensitivity Tests; Drug Resistance, Bacterial; Pneumonia, Mycoplasma
PubMed: 37284499
DOI: 10.3389/fcimb.2023.1186017 -
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 -
Toxins May 2021Macrolides are a diverse class of hydrophobic compounds characterized by a macrocyclic lactone ring and distinguished by variable side chains/groups. Some of the most... (Review)
Review
Macrolides are a diverse class of hydrophobic compounds characterized by a macrocyclic lactone ring and distinguished by variable side chains/groups. Some of the most well characterized macrolides are toxins produced by marine bacteria, sea sponges, and other species. Many marine macrolide toxins act as biomimetic molecules to natural actin-binding proteins, affecting actin polymerization, while other toxins act on different cytoskeletal components. The disruption of natural cytoskeletal processes affects cell motility and cytokinesis, and can result in cellular death. While many macrolides are toxic in nature, others have been shown to display therapeutic properties. Indeed, some of the most well known antibiotic compounds, including erythromycin, are macrolides. In addition to antibiotic properties, macrolides have been shown to display antiviral, antiparasitic, antifungal, and immunosuppressive actions. Here, we review each functional class of macrolides for their common structures, mechanisms of action, pharmacology, and human cellular targets.
Topics: Animals; Anti-Bacterial Agents; Cytoskeleton; Humans; Hydrophobic and Hydrophilic Interactions; Macrolides; Marine Toxins
PubMed: 34065929
DOI: 10.3390/toxins13050347 -
Angewandte Chemie (International Ed. in... Jun 2016Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades... (Review)
Review
Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human-pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last-resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled "Combat drug resistance: no action today means no cure tomorrow" triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.
Topics: Anti-Bacterial Agents; Bacteria; Bacterial Proteins; Drug Design; Drug Resistance, Multiple, Bacterial; Macrolides; Molecular Dynamics Simulation; Organophosphates; Oxazoles; Oxazolidinones; Structure-Activity Relationship
PubMed: 27000559
DOI: 10.1002/anie.201506818 -
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 -
Postgraduate Medicine Sep 2017While there is evidence for cardiac arrhythmias associated with macrolide and fluoroquinolone antibiotics, there is still debate among health care providers as to... (Review)
Review
While there is evidence for cardiac arrhythmias associated with macrolide and fluoroquinolone antibiotics, there is still debate among health care providers as to whether this risk of arrhythmia is overstated. A joint panel of the US Food and Drug Administration suggested that macrolide and fluoroquinolone labels need much stronger warnings regarding the possible serious adverse cardiac effects associated with these antibiotics, especially since they are so widely prescribed. And while health care providers may differ on the pertinence of the cardiac risks associated with antibiotic use, they can undoubtedly minimize the cardiac effects that are associated with these antibiotics by paying attention to the cardiac risk factors and drug history associated with the patient. Relevant studies for our review were identified from a PubMed search using keywords and combined word searches involving macrolides, fluoroquinolones, and cardiac arrhythmias. We attempted to include as many recent (>2015) articles as possible. We included case reports, randomized, controlled trials, observational studies, case-control studies, systematic reviews, and retrospective studies. Underlying cardiac issues can predispose patients to harmful cardiac side effects that can be exacerbated in the presence of antibiotics. The health care provider should rule out any risk factor associated with antibiotic-induced cardiac arrhythmia in the event that a patient does need a macrolide or fluoroquinolone antibiotic. Rigorous patient evaluation and a detailed patient history, including short and long term medication use, is the likely key to reducing any risk of cardiac arrhythmias associated with macrolides and fluoroquinolones. Clinicians should be cautious when prescribing macrolide and fluoroquinolone medications to patients with risk factors that may lead to antibiotic-induced cardiac arrhythmias, including a slow heart rate and those that are taking medications to treat arrhythmias.
Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Arrhythmias, Cardiac; Bacterial Infections; Case-Control Studies; Female; Fluoroquinolones; Humans; Macrolides; Male; Middle Aged; Retrospective Studies; Risk Factors; United States
PubMed: 28770640
DOI: 10.1080/00325481.2017.1362938 -
Expert Review of Clinical Pharmacology Mar 2018Until recently considered as a minor health problem, the role of bronchiectasis is now increasingly recognized. New specific drugs are being approved for treatment of... (Review)
Review
Until recently considered as a minor health problem, the role of bronchiectasis is now increasingly recognized. New specific drugs are being approved for treatment of bronchiectasis. Possibly they will offer better perspectives to bronchiectatic subjects with evolving course. Areas covered: We provide an overview of aetiopathogenesis, clinics and non-pharmacological management, extending the topic of pharmacological treatment. Present therapies were extrapolated from other chronic lung diseases, but newer promising specific drugs are being awaited. Therapy aims at improving mobilisation of bronchial secretions and, if any, reversing airflow obstruction. Antibiotics are indicated to treat exacerbations, eradicate or reduce sputum bacterial load. Expert commentary: Over the last years evidence is mounted that bronchiectatic subjects with accelerated course of disease should be referred to secondary and tertiary centres. This requires increased awareness on the role and the frequency of bronchiectasis in primary care. Long-term continuous or cyclical use of antibiotics is recommended to stabilize or improve the course of evolving disease. Macrolides are a currently preferred option. Inhaled antibiotics are gaining importance and are the object of ongoing research interest. Practical challenges of inhaled antibiotic treatment remain the need of defining the best therapeutic regimen and optimizing true adherence.
Topics: Administration, Inhalation; Airway Obstruction; Anti-Bacterial Agents; Bronchiectasis; Drug Design; Humans; Macrolides; Medication Adherence; Sputum
PubMed: 29268637
DOI: 10.1080/17512433.2018.1421064 -
Indian Journal of Medical Microbiology 2023As a major causative pathogen of community-acquired pneumonia, Mycoplasma pneumoniae (M. pneumoniae) can cause both upper and lower respiratory tract inflammation as...
BACKGROUND/PURPOSE
As a major causative pathogen of community-acquired pneumonia, Mycoplasma pneumoniae (M. pneumoniae) can cause both upper and lower respiratory tract inflammation as well as extrapulmonary syndromes, especially in infants and the elderly. The emergence of macrolide-resistance has significant effects on the treatment of relevant diseases in children. This study aimed to analyze the genotypes and the macrolide resistance-associated mutations in M. pneumoniae sampled from the pediatric patients in Henan, China.
METHODS
A segment of gene on the 23S rRNA was amplified and sequenced to detect the mutations related to macrolide resistance. Molecular typing was performed by the method named multiple locus variable-number tandem repeat analysis (MLVA) for macrolide-susceptible and macrolide-resistant specimens.
RESULTS
Among the M. pneumoniae-positive samples, 95.7% (111/116) had macrolide-resistant mutation, and all of them consisted of the A2063G mutation. There were only two MLVA types identified in this study, type 4-5-7-2 (51/92, 55.4%) and type 3-5-6-2 (41/92, 44.6%).
CONCLUSION
There was no correlation between MLVA types and macrolide resistance (P > 0.05).
Topics: Infant; Humans; Child; Aged; Mycoplasma pneumoniae; Anti-Bacterial Agents; Pneumonia, Mycoplasma; Macrolides; Drug Resistance, Bacterial; Molecular Typing; China
PubMed: 37945129
DOI: 10.1016/j.ijmmb.2023.100435 -
International Journal of Antimicrobial... Feb 2022Rare actinomycetes are a source of numerous diverse, biologically active secondary metabolites, including macrolides, which have been shown to display several antibiotic... (Review)
Review
Rare actinomycetes are a source of numerous diverse, biologically active secondary metabolites, including macrolides, which have been shown to display several antibiotic activities. The bioactivities and representative structures of 26 groups of macrolides from rare actinomycetes are presented in this review. The most interesting groups, with a wide range of biological activities, are ammocidins, bafilomycins, neomaclafungins, rosaramicins, spinosyns, and tiacumicins. Most macrolides are from the genus, Micromonospora, with smaller contributions from genera such as Saccharothrix, Amycolatopsis, Nocardiopsis and Catenulispora. These macrolides display unique cytotoxic, antibacterial, antifungal, antimicrobial, insecticidal, anti-trypanosomal, antimalarial, antiprotozoal, antimycobacterial and anti-herpetic activity. Considering their bioactivities and diverse structures, macrolides from rare actinomycetes warrant further investigation for future applications in medicine. This work highlights the bioactivities and structures of important classes of macrolides from rare actinomycetes that are already marketed or could be used in medicine in the future.
Topics: Actinobacteria; Actinomyces; Anti-Bacterial Agents; Antifungal Agents; Macrolides
PubMed: 35041941
DOI: 10.1016/j.ijantimicag.2022.106523 -
Journal of the Formosan Medical... Jun 2020Mycobacterium avium complex (MAC) is the major pathologic nontuberculous mycobacteria causing lung disease (LD) in humans worldwide. Although the burden of MAC-LD has... (Review)
Review
Mycobacterium avium complex (MAC) is the major pathologic nontuberculous mycobacteria causing lung disease (LD) in humans worldwide. Although the burden of MAC-LD has increased over the past two decades, treatment remains difficult because of intolerance of long-term antibiotics, lack of adherence to guidelines, and disease recurrence. The current guidelines recommend antibiotic initiation for patients with MAC-LD and severe disease and in those with disease progression. Thus, physicians should consider antibiotic treatment for patients with MAC-LD and cavitary pulmonary lesions or symptomatic non-cavitary nodular bronchiectasis pattern at initial visits and also for those with clinical deterioration during follow-up. The standard three-drug regimen should be macrolide, rifamycin, and ethambutol. Physicians should monitor side effects in patients and maintain the regimen for 12 months, beginning from when sputum conversion has been obtained. With adherence to guideline-based therapy, treatment is successful in two thirds of treatment-naïve patients without macrolide resistance. Without adherence, macrolide resistance can occur, which leads to poor outcomes in patients with MAC-LD. Although the discovery of new treatment options is warranted, adherence to guidelines remains most crucial in treating patients with MAC-LD. It is worth mentioning that the majority of current recommendations are based on observational studies or small-scale clinical trials.
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Humans; Lung Diseases; Macrolides; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Retrospective Studies
PubMed: 32446754
DOI: 10.1016/j.jfma.2020.05.006