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ELife Jun 2022Phenotypic variations between individual microbial cells play a key role in the resistance of microbial pathogens to pharmacotherapies. Nevertheless, little is known...
Phenotypic variations between individual microbial cells play a key role in the resistance of microbial pathogens to pharmacotherapies. Nevertheless, little is known about cell individuality in antibiotic accumulation. Here, we hypothesise that phenotypic diversification can be driven by fundamental cell-to-cell differences in drug transport rates. To test this hypothesis, we employed microfluidics-based single-cell microscopy, libraries of fluorescent antibiotic probes and mathematical modelling. This approach allowed us to rapidly identify phenotypic variants that avoid antibiotic accumulation within populations of , , and . Crucially, we found that fast growing phenotypic variants avoid macrolide accumulation and survive treatment without genetic mutations. These findings are in contrast with the current consensus that cellular dormancy and slow metabolism underlie bacterial survival to antibiotics. Our results also show that fast growing variants display significantly higher expression of ribosomal promoters before drug treatment compared to slow growing variants. Drug-free active ribosomes facilitate essential cellular processes in these fast-growing variants, including efflux that can reduce macrolide accumulation. We used this new knowledge to eradicate variants that displayed low antibiotic accumulation through the chemical manipulation of their outer membrane inspiring new avenues to overcome current antibiotic treatment failures.
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Proteins; Macrolides; Microbial Sensitivity Tests; Pseudomonas aeruginosa
PubMed: 35670099
DOI: 10.7554/eLife.74062 -
International Journal of Psychiatry in... Mar 2022This review aimed to explore and summarise available cases of delirium suspected to be associated with the use of macrolide antibiotics reported in the literature and... (Review)
Review
OBJECTIVE
This review aimed to explore and summarise available cases of delirium suspected to be associated with the use of macrolide antibiotics reported in the literature and the United States Food and Drug Administration's Adverse Event Reporting System (FAERS) database.
METHODS
Electronic searches of the literature were conducted in four online databases: PubMed/MEDLINE, Scopus, Web of Science and Serbian Citation Index (SCIndeks). A search of FAERS database was also conducted to supplement the findings of the literature search. Descriptive statistics, narrative summation and tabulation of the extracted data were made.
RESULTS
Cases of delirium which satisfied inclusion criteria were found for clarithromycin, azithromycin, erythromycin and telithromycin. Delirium was described in patients of various age groups, including children. Drug-drug interactions may have contributed to its occurrence in some of the cases. Average time to onset of delirium was 2.5 days for azithromycin and 3.3 days for clarithromycin.
CONCLUSIONS
Considering that these drugs may be a possible cause of delirium, clinicians should be aware that timely recognition of this possible side effect can lead to earlier discontinuation of the culprit drug, reduce time spent in a delirious state and improve patients' outcomes.KEY POINTSCases of delirium which satisfied inclusion criteria were found for clarithromycin, azithromycin, erythromycin and telithromycin.Cases of delirium were described in patients of various age groups, including children.Drug-drug interactions may have contributed to the occurrence of delirium in some of the cases.Time to onset of delirium ranged from 2 to 3.5 days (mean: 2.5 days) for azithromycin and from 1 to 7 days (mean: 3.3 days) for clarithromycin.Cessation of the macrolide antibiotic seems to be the best management strategy, although some of the patients may, in addition, require antipsychotics.
Topics: Anti-Bacterial Agents; Azithromycin; Child; Clarithromycin; Delirium; Erythromycin; Humans
PubMed: 33026877
DOI: 10.1080/13651501.2020.1828933 -
Journal of Microbiology, Immunology,... Jun 2023Macrolide-resistant Mycoplasma pneumoniae (MRMP) infection is increasing worldwide. However, its clinical significance is still uncertain.
The clinical significance of and the factors associated with macrolide resistance and poor macrolide response in pediatric Mycoplasma pneumoniae infection: A retrospective study.
BACKGROUND
Macrolide-resistant Mycoplasma pneumoniae (MRMP) infection is increasing worldwide. However, its clinical significance is still uncertain.
METHODS
The data of the Laboratory Medicine Department of Chang Gung Memorial Hospital in northern Taiwan was searched for children with molecular confirmed macrolide-susceptible Mycoplasma pneumoniae (MSMP) and MRMP infections between January 2011 and December 2018. The clinical features, laboratory data, and chest image presentations were compared between patients with MRMP and MSMP infections and between patients with good and poor macrolide response, respectively.
RESULTS
Records from 158 patients were recovered. Of the enrolled patients 34 (22%) suffered MRMP infection, 27 (17%) had pleural effusions, and 47 (32%) had poor macrolide response. The macrolide resistance rate was 12% in 2011, 20% between 2015 and 2016, and 50% between 2017 and 2018, respectively. Other than a poor macrolide response, the MRMP and MSMP infections are clinically indistinguishable. The presence of pleural effusion and MRMP infections were found to be independently associated with a poor macrolide response, with odds ratios (95% confidence interval) of 14.3 (4.9-42.0) and 14.6 (5.4-40), respectively. The macrolide resistance rate of the patients with a poor macrolide response was 49% and 18% among all the patients enrolled and the patients with a pleural effusion, respectively.
CONCLUSION
The macrolide resistance rate had possibly increased in recent years in Taiwan and should be continuously monitored. In addition, the macrolide response could be misleading in predicting a macrolide resistance especially for the patients with a pleural effusion.
Topics: Child; Humans; Anti-Bacterial Agents; Pneumonia, Mycoplasma; Macrolides; Retrospective Studies; Clinical Relevance; Drug Resistance, Bacterial; Mycoplasma pneumoniae; Pleural Effusion
PubMed: 36737359
DOI: 10.1016/j.jmii.2023.01.010 -
Journal of Medicinal Chemistry Jun 2020This is a review of the macrolide and ketolide field focusing on differentiating the pharmacodynamics and especially the toxicology of the macrolides and ketolides. We...
This is a review of the macrolide and ketolide field focusing on differentiating the pharmacodynamics and especially the toxicology of the macrolides and ketolides. We emphasize the diversity in pharmacodynamics and toxicity of the macrolides and ketolides, resulting from even small structural changes, which makes it important to consider the various different compounds separately, not necessarily as a class. The ketolide, telithromycin, was developed because of rising bacterial macrolide resistance but was withdrawn postapproval after visual disturbances, syncope, myasthenia gravis, and hepatotoxicity were noted. These diverse adverse effects could be attributed to inhibition of nicotinic acetylcholine receptors. Solithromycin, a later generation ketolide, was effective in treating bacterial pneumonia, but it was not approved by the U.S. Food and Drug Administration owing, in part, to its structural similarity to telithromycin. This Miniperspective describes that structurally similar macrolides/ketolides have clearly mechanistically distinct effects. Understanding these effects could help in developing and securing regulatory approval of a new macrolide/ketolide that is active against macrolide-resistant pathogenic bacteria.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Drug Resistance, Bacterial; Drug-Related Side Effects and Adverse Reactions; Humans; Ketolides; Macrolides
PubMed: 31644280
DOI: 10.1021/acs.jmedchem.9b01159 -
World Journal of Microbiology &... Sep 2023A comparative analysis between water and sediment can provide better information to understand the dynamics of the inhabitant microbiome and their respective antibiotic...
A comparative analysis between water and sediment can provide better information to understand the dynamics of the inhabitant microbiome and their respective antibiotic resistance genes of a river. Therefore, the present investigation was carried to explore the limited information available on bacterial microbiome and their predictive antibiotic resistance genes (ARGs) from water and sediment of the Ganga River. The study utilized the NGS-based sequences previously submitted under the accession number (PRJNA847424 and PRJNA892876). Overall analysis revealed that twenty phyla and fifty-four genera were shared between the water and sediment of the Ganga River. Of them, nine phyla and nineteen genera were observed as significantly different (p-value < 0.05). Where the majority of the genera were associated with the sediment samples over the water that identify the sediment samples as more diverse for species richness. Similarly, seventy-six ARGs were shared between water and sediment samples. Of the ten abundant antibiotic resistance pathways, seven were relatively abundant in sediment samples as compared to the water. Vancomycin resistance genes were significantly more abundant among sediment samples, whereas β-lactam resistance genes were equally distributed in water and sediment samples. The network analysis further revealed that five genera (Flavobacterium, Pseudomonas, Acinetobacter, Candidatus_divison CL5003, and Candidatus_division SWB02) showed a significantly positive correlation with six antibiotic resistance pathways (β-lactam, vancomycin, multidrug resistance, tetracycline, aminoglycoside, and macrolide resistance pathways). The study comes out with several findings where sediment may be considered as a more atrocious habitat for evolving the resistance mechanisms against threatful antibiotics over the water samples of the Ganga River.
Topics: Anti-Bacterial Agents; Water; Rivers; Drug Resistance, Bacterial; Macrolides; Vancomycin; India
PubMed: 37656255
DOI: 10.1007/s11274-023-03730-0 -
Revue Medicale Suisse Nov 2022Macrolides are commonly used antibiotics due to their broad spectrum of activity and good bioavailability. More recently, they have been shown to be effective in certain... (Review)
Review
Macrolides are commonly used antibiotics due to their broad spectrum of activity and good bioavailability. More recently, they have been shown to be effective in certain chronic lung diseases by reducing exacerbation frequency. This narrative review examines the scientific evidence and international recommendation for immunomodulatory macrolides therapy in the most frequent chronic respiratory disorders.
Topics: Humans; Macrolides; Lung Diseases; Anti-Bacterial Agents
PubMed: 36416507
DOI: 10.53738/REVMED.2022.18.805.2206 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Aug 2023Tacrolimus (FK506) is a 23-membered macrolide with immunosuppressant activity that is widely used clinically for treating the rejection after organ transplantation. The... (Review)
Review
Tacrolimus (FK506) is a 23-membered macrolide with immunosuppressant activity that is widely used clinically for treating the rejection after organ transplantation. The research on tacrolimus production was mainly focused on biosynthesis methods, within which there are still some bottlenecks. This review summarizes the progress made in tacrolimus biosynthesis modification of metabolic pathways and control of fermentation process, with the hope to address the technical bottlenecks for tacrolimus biosynthesis and improve tacrolimus production by fermentation engineering and metabolic engineering.
Topics: Tacrolimus; Immunosuppressive Agents; Fermentation; Macrolides; Anti-Bacterial Agents
PubMed: 37622350
DOI: 10.13345/j.cjb.220994 -
Frontiers in Cellular and Infection... 2023With the widespread use of macrolide antibiotics in China, common pathogens causing children's infections, such as , (including , ), , , and , have shown varying... (Review)
Review
With the widespread use of macrolide antibiotics in China, common pathogens causing children's infections, such as , (including , ), , , and , have shown varying degrees of drug resistance. In order to provide such problem and related evidence for rational use of antibiotics in clinic, we reviewed the drug resistance of common bacteria to macrolides in children recent 20 years.
Topics: Drug Resistance, Bacterial; Macrolides; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Humans; Child; China
PubMed: 37637457
DOI: 10.3389/fcimb.2023.1181633 -
International Journal of Molecular... Oct 2020Macrolide antibiotics are macrocyclic compounds that are clinically used and prescribed for the treatment of upper and lower respiratory tract infections. They inhibit... (Review)
Review
Macrolide antibiotics are macrocyclic compounds that are clinically used and prescribed for the treatment of upper and lower respiratory tract infections. They inhibit the synthesis of bacterial proteins by reversible binding to the 23S rRNA at or near the peptidyl transferase center. However, their excellent antibacterial profile was largely compromised by the emergence of bacterial resistance. Today, fighting resistance to antibiotics is one of the greatest challenges in medicinal chemistry. Considering various physicochemical properties of macrolides, understanding their structure and interactions with macromolecular targets is crucial for the design of new antibiotics efficient against resistant pathogens. The solid-state structures of some macrolide-ribosome complexes have recently been solved, throwing new light on the macrolide binding mechanisms. On the other hand, a combination of NMR spectroscopy and molecular modeling calculations can be applied to study free and bound conformations in solution. In this article, a description of advanced physicochemical methods for elucidating the structure and interactions of macrolide antibiotics in solid state and solution will be provided, and their principal advantages and drawbacks will be discussed.
Topics: Anti-Bacterial Agents; Computer Simulation; Cryoelectron Microscopy; Crystallography, X-Ray; Macrolides; Magnetic Resonance Spectroscopy; Molecular Dynamics Simulation; Ribosomes
PubMed: 33096889
DOI: 10.3390/ijms21207799 -
Environmental Science and Pollution... Apr 2022Macrolide antibiotics (MAs), as a typical emerging pollutant, are widely detected in environmental media. When entering the environment, MAs can interfere with the... (Review)
Review
Macrolide antibiotics (MAs), as a typical emerging pollutant, are widely detected in environmental media. When entering the environment, MAs can interfere with the growth, development and reproduction of organisms, which has attracted extensive attention. However, there are few reviews on the occurrence characteristics, migration and transformation law, ecotoxicity and related removal technologies of MAs in the environment. In this work, combined with the existing relevant research, the migration and transformation law and ecotoxicity characteristics of MAs in the environment are summarized, and the removal mechanism of MAs is clarified. Currently, most studies on MAs are based on laboratory simulation experiments, and there are few studies on the migration and transformation mechanism between multiphase states. In addition, the cost of MAs removal technology is not satisfactory. Therefore, the following suggestions are put forward for the future research direction. The migration and transformation process of MAs between multiphase states (such as soil-water-sediment) should be focused on. Apart from exploring the new treatment technology of MAs, the upgrading and coupling of existing MAs removal technologies to meet emission standards and reduce costs should also be concerned. This review provides some theoretical basis and data support for understanding the occurrence characteristics, ecotoxicity and removal mechanism of MAs.
Topics: Anti-Bacterial Agents; Environmental Pollutants; Macrolides; Soil; Water Pollutants, Chemical
PubMed: 35067882
DOI: 10.1007/s11356-021-18251-2