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 via 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.
Tacrolimus ; Immunosuppressive Agents ; Fermentation ; Macrolides ; Anti-Bacterial Agents

Macrolide and corticosteroid resistance has been reported in patients with Mycoplasma pneumoniae (MP) pneumonia (MPP). MP clearance is difficult to achieve through antibiotic treatment in sensitive patients with severe MPP (SMPP). SMPP in children might progress to airway remodeling and even bronchiolitis/bronchitis obliterans. Therefore, identifying serum biomarkers that indicate MPP progression and exploring new targeted drugs for SMPP treatment require urgency. In this study, serum samples were collected from patients with general MPP (GMPP) and SMPP to conduct proteomics profiling. The Fc fragment of the IgG-binding protein (FCGBP) was identified as the most promising indicator of SMPP. Biological enrichment analysis indicated uncontrolled inflammation in SMPP. ELISA results proved that the FCGBP level in patients with SMPP was substantially higher than that in patients with GMPP. Furthermore, the FCGBP levels showed a decreasing trend in patients with GMPP but the opposite trend in patients with SMPP during disease progression. Connectivity map analyses identified 25 possible targeted drugs for SMPP treatment. Among them, a mechanistic target of rapamycin kinase (mTOR) inhibitor, which is a macrolide compound and a cell proliferation inhibitor, was the most promising candidate for targeting SMPP. To our knowledge, this study was the first proteomics-based characterization of patients with SMPP and GMPP.
Biomarkers ; Carrier Proteins ; Child ; Humans ; Immunoglobulin Fc Fragments ; Immunoglobulin G ; Macrolides ; Mycoplasma pneumoniae ; Pneumonia, Mycoplasma/drug therapy* ; Proteomics

Child ; Humans ; Pneumonia, Mycoplasma/epidemiology* ; Macrolides/therapeutic use* ; Singapore/epidemiology* ; Child, Hospitalized ; Mycoplasma pneumoniae ; Anti-Bacterial Agents/therapeutic use* ; Drug Resistance, Bacterial ; Community-Acquired Infections/drug therapy*

14- to 16-membered macrolide antibiotics (MA) are clinically important anti-infective drugs. With the rapid emergence of bacterial resistance, there is an urgent need to develop novel MA to counter drug-resistant bacteria. The targeted optimization of MA can be guided by analyzing the interaction between the MA and its ribosomal targets, and the desired MA derivatives can be obtained efficiently when combining with the rapidly developed metabolic engineering approaches. In the past 30 years, metabolic engineering approaches have shown great advantages in engineering the biosynthesis of MA to create new derivatives and to improve their production. These metabolic engineering approaches include modification of the structural domains of the polyketide synthase (PKS) and post-PKS modification enzymes as well as combinatorial biosynthesis. In addition, the R&D (including the evaluation of its antimicrobial activities and the optimization through metabolic engineering) of carrimycin, a new 16-membered macrolide drug, are described in details in this review.
Anti-Bacterial Agents ; Bacteria/genetics* ; Macrolides ; Metabolic Engineering ; Polyketide Synthases

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.
Anti-Bacterial Agents ; Biodegradation, Environmental ; Macrolides

OBJECTIVES: Genetic determinants conferring resistance to macrolide, lincosamide, and streptogramin B (MLSB) via ribosomal modification such as, erm, msrA/B and ereA/B genes are distributed in bacteria. The main goals of this work were to evaluate the dissemination of MLSB resistance phenotypes and genotypes in methicillin-resistant Staphylococcus aureus (MRSA) isolates collected from clinical samples. METHODS: A total of 106 MRSA isolates were studied. Isolates were recovered from 3 hospitals in Tehran between May 2016 to July 2017. The prevalence of MLSB-resistant strains were determined by D-test, and then M-PCR was performed to identify genes encoding resistance to macrolides, lincosamides, and streptogramins in the tested isolates. RESULTS: The frequency of constitutive resistance MLSB, inducible resistance MLSB and MSB resistance were 56.2%, 22.9%, and 16.6%, respectively. Of 11 isolates with the inducible resistance MLSB phenotype, ermC, ermB, ermA and ereA were positive in 81.8%, 63.6%, 54.5% and 18.2% of these isolates, respectively. In isolates with the constitutive resistance MLSB phenotype, the prevalence of ermA, ermB, ermC, msrA, msrB, ereA and ereB were 25.9%, 18.5%, 44.4%, 0.0%, 0.0%, 11.1% and 0.0%, respectively. CONCLUSION: Clindamycin is commonly administered in severe MRSA infections depending upon the antimicrobial susceptibility findings. This study showed that the D-test should be used as an obligatory method in routine disk diffusion assay to detect inducible clindamycin resistance in MRSA so that effective antibiotic treatment can be provided.
Bacteria ; Clindamycin ; Diffusion ; Drug Resistance ; Genotype ; Lincosamides ; Macrolides ; Methicillin-Resistant Staphylococcus aureus ; Methods ; Phenotype ; Prevalence ; Staphylococcus aureus ; Staphylococcus ; Streptogramin B ; Streptogramins

The pathogen Mycobacterium avium complex (MAC) is the most common cause of nontuberculous mycobacterial pulmonary disease worldwide. The decision to initiate long-term antibiotic treatment is difficult for the physician due to inconsistent disease progression and adverse effects associated with the antibiotic treatment. The prognostic factors for the progression of MAC pulmonary disease are low body mass index, poor nutritional status, presence of cavitary lesion(s), extensive disease, and a positive acid-fast bacilli smear. A regimen consisting of macrolides (clarithromycin or azithromycin) with rifampin and ethambutol has been recommended; this regimen significantly improves the treatment of MAC pulmonary disease and should be maintained for at least 12 months after negative sputum culture conversion. However, the rates of default and disease recurrence after treatment completion are still high. Moreover, treatment failure or macrolide resistance can occur, although in some refractory cases, surgical lung resection can improve treatment outcomes. However, surgical resection should be carefully performed in a well-equipped center and be based on a rigorous risk-benefit analysis in a multidisciplinary setting. New therapies, including clofazimine, inhaled amikacin, and bedaquiline, have shown promising results for the treatment of MAC pulmonary disease, especially in patients with treatment failure or macrolide-resistant MAC pulmonary disease. However, further evidence of the efficacy and safety of these new treatment regimens is needed. Also, a new consensus is needed for treatment outcome definitions as widespread use of these definitions could increase the quality of evidence for the treatment of MAC pulmonary disease.
Amikacin ; Body Mass Index ; Clofazimine ; Consensus ; Disease Progression ; Ethambutol ; Humans ; Lung ; Lung Diseases ; Macrolides ; Mycobacterium avium Complex* ; Mycobacterium avium* ; Mycobacterium* ; Nontuberculous Mycobacteria ; Nutritional Status ; Recurrence ; Rifampin ; Sputum ; Treatment Failure ; Treatment Outcome

The fcl gene encodes GDP-fucose synthase, which catalyzes two-step differential isomerase and reductase reactions in the synthesis of GDP-L-fucose from GDP-D-mannose. It also participates in the biosynthesis of amino sugar and ribose sugar, and is one of the key enzymes to regulate the metabolism of sugar and nucleotides in organisms. The presence of fcl gene in Saccharopolyspora pogona was found through sequencing result of genome. The mutant S. pogona-fcl and S. pogona-Δfcl were constructed by gene engineering technology. The results showed that the gene had an effects on growth and development, protein expression and transcriptional level, insecticidal activity, and biosynthesis of butenyl-spinosyn of Saccharopolyspora pogona. The results of HPLC analysis showed that the yield of butenyl-spinosyn in S. pogona-Δfcl was 130% compared with that in S. pogona, which reduced by 25% in S. pogona-fcl. The results of determination of insecticidal activity showed that S. pogona-Δfcl had a stronger insecticidal activity against Helicoverpa armigera than that of S. pogona, while the S. pogona-fcl had a lower insecticidal activity against Helicoverpa armigera compared with S. pogona. Scanning electron microscopy (SEM) was used to observe the morphology of the mycelia. It was found that the surface of the S. pogona-Δfcl was wrinkled, and the mycelium showed a short rod shape. There was no significant difference in mycelial morphology between S. pogona-fcl and S. pogona. Aboved all showed that deletion of fcl gene in S. pogona hindered the growth and development of mycelia, but was beneficial to increase the biosynthesis of butenyl-spinosyn and improve insecticidal activity. Whereas the fcl gene over-expression was not conducive to the biosynthesis of butenyl-spinosyn and reduced their insecticidal activity. SDS-PAGE results showed that the difference of protein expression among the three strains was most obvious at 96 hours, which was identified by real-time fluorescence quantitative polymerase chain reaction, the results showed that there were significant differences of related genes in transcriptional levels among the three strains. Based on the results of the study, a network metabolic control map was constructed to analyze the effect of fcl gene on growth and the regulation pathway of butenyl-spinosyn biosynthesis, which provided an experimental basis for revealing the regulation mechanism of butenyl-spinosyn biosynthesis and related follow-up studies.
Bacterial Proteins ; Genetic Engineering ; Insecticides ; Macrolides ; Saccharopolyspora

Mycobacterium abscessus is the second most important pathogen in pulmonary disease caused by nontuberculous mycobacteria (NTM), following Mycobacterium avium. Mycobacterium abscessus is classified into three subspecies: M. abscessus subsp. abscessus, M. abscessus subsp. massiliense, and M. abscessus subsp. bolletii. Mycobacterium abscessus is the most difficult to treat NTM due to its resistance to many antibiotics. Treatment should include an initial regimen of 2–3 injectable and oral antibiotics for several weeks or months, followed by inhaled amikacin and 1–3 oral antibiotics, depending on the subspecies and drug susceptibility patterns, including macrolide susceptibility. The continuation phase should be continued for a minimum of 12 months after culture conversion. Suitable injectable antibiotics include amikacin, imipenem, cefoxitin, and tigecycline, while oral antibiotics include macrolides (azithromycin or clarithromycin), clofazimine, linezolid, and moxifloxacin. Surgery can be a useful adjunctive therapy for some patients with refractory disease. However, the overall treatment prognosis is still unsatisfactory. Therefore, novel and more effective interventions are required for the treatment of M. abscessus pulmonary disease.
Amikacin ; Anti-Bacterial Agents ; Cefoxitin ; Clofazimine ; Humans ; Imipenem ; Linezolid ; Lung Diseases ; Macrolides ; Mycobacterium avium ; Mycobacterium ; Nontuberculous Mycobacteria ; Prognosis

Although Mycoplasma pneumoniae pneumonia (MPP) has been generally susceptible to macrolides, the emergence of macrolide-resistant MPP (MRMP) has made its treatment challenging. MRMP rapidly spread after the 2000s, especially in East Asia. MRMP is more common in children and adolescents than in adults, which is likely related to the frequent use of macrolides for treating M. pneumoniae infections in children. MRMP is unlikely to be related to clinical, laboratory, or radiological severity, although it likely prolongs the persistence of symptoms and the length of hospital stay. Thereby, it causes an increased burden of the disease and poor quality of life for the patient as well as a societal socioeconomic burden. To date, the only alternative treatments for MRMP are secondary antimicrobials such as tetracyclines (TCs) or fluoroquinolones (FQs) or systemic corticosteroids; however, the former are contraindicated in children because of concerns about potential adverse events (i.e., tooth discoloration or tendinopathy). A few guidelines recommended TCs or FQs as the second-line drug of choice for treating MRMP. However, there have been no evidence-based guidelines. Furthermore, safety issues have not yet been resolved. Therefore, this article aimed to review the benefits and risks of therapeutic alternatives for treating MRMP in children and review the recommendations of international or regional guidelines and specific considerations for their practical application.
Adolescent ; Adrenal Cortex Hormones ; Adult ; Child ; Drug Resistance ; Far East ; Fluoroquinolones ; Humans ; Length of Stay ; Macrolides ; Mycoplasma pneumoniae ; Mycoplasma ; Pneumonia ; Pneumonia, Mycoplasma ; Quality of Life ; Risk Assessment ; Tetracycline ; Tetracyclines ; Tooth Discoloration