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Sheng Wu Gong Cheng Xue Bao = Chinese... May 202114- 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... (Review)
Review
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.
Topics: Anti-Bacterial Agents; Bacteria; Macrolides; Metabolic Engineering; Polyketide Synthases
PubMed: 34085452
DOI: 10.13345/j.cjb.200686 -
Current Topics in Medicinal Chemistry 2017Macrolides, polyketide natural products, and their 15-membered semi-synthetic derivatives are composed of substituted macrocyclic lactone ring and used primarily as... (Review)
Review
Macrolides, polyketide natural products, and their 15-membered semi-synthetic derivatives are composed of substituted macrocyclic lactone ring and used primarily as potent antibiotics. Recently their usefulness was extended to antimalarial and anti-inflammatory area. Hybrid macrolides presented in this article are the next generation semi-synthetic compounds that combine pharmacophores from antibacterial, antimalarial and anti-inflammatory area with 14- and 15-membered azalide scaffolds. Antibacterial azalide hybrids with sulphonamides showed improved activity against resistant streptococci while quinolone conjugates demonstrated full coverage of respiratory pathogens including macrolide resistant strains and their efficacy was confirmed in mouse pneumonia model. Antimalarial macrolide hybrids, mainly involving (chloro)quinoline pharmacophores, showed outstanding activity against chloroquine resistant strains, favourable pharmacokinetics, promising in vivo efficacy as well as encouraging developmental potential. Anti-inflammatory hybrids were obtained by combining macrolides with corticosteroid and non-steroidal anti-inflammatory drugs. They were found active in in vivo animal models of locally induced inflammation, asthma, inflammatory bowel disease and rheumatoid arthritis and demonstrated improved safety over parent steroid drugs. Overall, macrolide hybrids possess significant potential to be developed as potent novel medicines in therapeutic areas of utmost pharmaceutical interest.
Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antimalarials; Bacteria; Drug Discovery; Humans; Inflammation; Macrolides; Malaria
PubMed: 27697049
DOI: 10.2174/1568026616666160927160036 -
MSphere Oct 2022Escherichia coli is intrinsically resistant to macrolides due to outer membrane impermeability, but may also acquire macrolide resistance genes by horizontal transfer....
Escherichia coli is intrinsically resistant to macrolides due to outer membrane impermeability, but may also acquire macrolide resistance genes by horizontal transfer. We evaluated the prevalence and types of acquired macrolide resistance determinants in pig clinical E. coli, and we assessed the ability of peptidomimetics to potentiate different macrolide subclasses against strains resistant to neomycin, a first-line antibiotic in the treatment of pig-enteric infections. The erythromycin MIC distribution was determined in 324 pig clinical E. coli isolates, and 62 neomycin-resistant isolates were further characterized by genome sequencing and MIC testing of azithromycin, spiramycin, tilmicosin, and tylosin. The impact on potency achieved by combining these macrolides with three selected peptidomimetic compounds was determined by checkerboard assays in six strains representing different genetic lineages and macrolide resistance gene profiles. Erythromycin MICs ranged from 16 to >1,024 μg/mL. Azithromycin showed the highest potency in wild-type strains (1 to 8 μg/mL), followed by erythromycin (16 to 128 μg/mL), tilmicosin (32 to 256 μg/mL), and spiramycin (128 to 256 μg/mL). Isolates with elevated MIC mainly carried (B), either alone or in combination with other acquired macrolide resistance genes, including (42), (C), (A), (B), and (G). All peptidomimetic-macrolide combinations exhibited synergy (fractional inhibitory concentration index [FICI] < 0.5) with a 4- to 32-fold decrease in the MICs of macrolides. Interestingly, the MICs of tilmicosin in wild-type strains were reduced to concentrations (4 to 16 μg/mL) that can be achieved in the pig intestinal tract after oral administration, indicating that peptidomimetics can potentially be employed for repurposing tilmicosin in the management of E. coli enteritis in pigs. Acquired macrolide resistance is poorly studied in Escherichia coli because of intrinsic resistance and limited antimicrobial activity in Gram-negative bacteria. This study reveals new information on the prevalence and distribution of macrolide resistance determinants in a comprehensive collection of porcine clinical E. coli from Denmark. Our results contribute to understanding the correlation between genotypic and phenotypic macrolide resistance in E. coli. From a clinical standpoint, our study provides an initial proof of concept that peptidomimetics can resensitize E. coli to macrolide concentrations that may be achieved in the pig intestinal tract after oral administration. The latter result has implications for animal health and potential applications in veterinary antimicrobial drug development in view of the high rates of antimicrobial-resistant E. coli isolated from enteric infections in pigs and the lack of viable alternatives for treating these infections.
Topics: Swine; Animals; Escherichia coli; Anti-Bacterial Agents; Azithromycin; Peptidomimetics; Macrolides; Tylosin; Drug Resistance, Bacterial; Spiramycin; Erythromycin; Escherichia coli Infections; Neomycin
PubMed: 36154672
DOI: 10.1128/msphere.00402-22 -
Current Topics in Medicinal Chemistry 2021Staphylococcus aureus (S. aureus), recognized as one of the deadliest pathogens responsible for nosocomial and community acquired infections, is highly contagious and... (Review)
Review
Staphylococcus aureus (S. aureus), recognized as one of the deadliest pathogens responsible for nosocomial and community acquired infections, is highly contagious and associated with significant morbidity and mortality. The increasing emergency and rapid spread of various forms of drug-resistant S. aureus have already posed a heavy burden on the world health system, but newfangled antibiotics are right now being created at a much slower pace than our developing requirement. Macrolides could inhibit protein synthesis by targeting the bacterial ribosome and are a class of basic and widely used antibacterial agents in clinical practice to control infections caused by various bacteria, including S. aureus. However, the emergence of bacterial resistance to macrolide antibiotics, particularly in Gram-positive bacteria such as macrolide-resistant S. aureus, has already become one of the significant obstacles for effective chemotherapy. Therefore, there is a critical need for the development of novel macrolide candidates. This review provides an overview of macrolide hybrids with potential activity against S. aureus, including drug-resistant forms developed in the recent decade, with special emphasis on the structure-activity relationships and mechanism of actions.
Topics: Anti-Bacterial Agents; Humans; Macrolides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship
PubMed: 33272187
DOI: 10.2174/1568026620999201203213733 -
The Lancet. Respiratory Medicine Jun 2020Critical illness is associated with immune dysregulation, characterised by concurrent hyperinflammation and immune suppression. Hyperinflammation can result in... (Review)
Review
Critical illness is associated with immune dysregulation, characterised by concurrent hyperinflammation and immune suppression. Hyperinflammation can result in collateral tissue damage and organ failure, whereas immune suppression has been implicated in susceptibility to secondary infections and reactivation of latent viruses. Macrolides are a class of bacteriostatic antibiotics that are used in the intensive care unit to control infections or to alleviate gastrointestinal dysmotility. Yet macrolides also have potent and wide-ranging immunomodulatory properties, which might have the potential to correct immune dysregulation in patients who are critically ill without affecting crucial antimicrobial defences. In this Review, we provide an overview of preclinical and clinical studies that point to the beneficial effects of macrolides in acute diseases relevant to critical care, and we discuss the possible underlying mechanisms of their immunomodulatory effects. Further studies are needed to explore the therapeutic potential of macrolides in critical illness, to identify subgroups of patients who might benefit from treatment, and to develop novel non-antibiotic macrolide derivatives with improved immunomodulatory properties.
Topics: Anti-Bacterial Agents; Critical Care; Humans; Immunomodulation; Macrolides
PubMed: 32526189
DOI: 10.1016/S2213-2600(20)30080-1 -
Environmental Geochemistry and Health Oct 2022The spread of antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs) has become an increasingly serious global public health issue. This study...
Distribution of quinolone and macrolide resistance genes and their co-occurrence with heavy metal resistance genes in vegetable soils with long-term application of manure.
The spread of antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs) has become an increasingly serious global public health issue. This study investigated the distribution characteristics and influencing factors of ARB and ARGs in greenhouse vegetable soils with long-term application of manure. Five typical ARGs, four heavy metal resistance genes (MRGs), and two mobile genetic elements (MGEs) were quantified by real-time quantitative polymerase chain reaction (qPCR). The amount of ARB in manure-improved soil greatly exceeded that in control soil, and the bacterial resistance rate decreased significantly with increases in antibiotic concentrations. In addition, the resistance rate of ARB to enrofloxacin (ENR) was lower than that of tylosin (TYL). Real-time qPCR results showed that long-term application of manure enhanced the relative abundance of ARGs in vegetable soils, and the content and proportion of quinolone resistance genes were higher than those of macrolide resistance genes. Redundancy analysis (RDA) showed that qepA and qnrS significantly correlated with total and available amounts of Cu and Zn, highlighting that certain heavy metals can influence persistence of ARGs. Integrase gene intI1 correlated significantly with the relative abundance of qepA, qnrS, and ermF, suggesting that intI1 played an important role in the horizontal transfer of ARGs. Furthermore, there was a weakly but not significantly positive correlation between specific detected MRGs and ARGs and MGEs. The results of this study enhance understanding the potential for increasing ARGs in manure-applied soil, assessing ecological risk and reducing the spread of ARGs.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anti-Bacterial Agents; Drug Resistance, Bacterial; Enrofloxacin; Genes, Bacterial; Integrases; Macrolides; Manure; Metals, Heavy; Quinolones; Soil; Soil Microbiology; Tylosin; Vegetables
PubMed: 34559332
DOI: 10.1007/s10653-021-01102-x -
Chest Jul 2022Long-term macrolide therapy has been shown to provide benefit to those with a range of chronic respiratory conditions. However, concerns remain about the impact of...
BACKGROUND
Long-term macrolide therapy has been shown to provide benefit to those with a range of chronic respiratory conditions. However, concerns remain about the impact of macrolide exposure on the carriage and abundance of antibiotic resistance genes within the oropharynx. The potential for onward transmission of resistance from macrolide recipients to their close contacts also is poorly understood.
RESEARCH QUESTION
Does long-term macrolide use impact carriage of resistance within the oropharyngeal microbiota in people with chronic respiratory conditions and risk of onward transmission to their close contacts?
STUDY DESIGN AND METHODS
Oropharyngeal swabs were collected from 93 individuals with chronic respiratory conditions, 53 of whom were receiving long-term macrolide therapy. An oropharyngeal swab also was collected from a close cohabiting contact of each patient. Detection and abundance of 10 macrolide-associated resistance genes with the potential to disseminate via horizontal gene transfer were assessed by quantitative polymerase chain reaction analysis.
RESULTS
Detection of resistance genes in macrolide recipients was comparable with that in nonrecipients. However, the normalized gene abundance of erm(B) was significantly higher in the macrolide recipient group (P = .045). Among the close contacts, no between-group differences in resistance gene detection or abundance were identified. Within-group analysis showed that the detection of erm(F) and mef in macrolide recipients, but not nonrecipients, was associated significantly with detection in close contacts (P = .003 and P = .004, respectively). However, between-group analysis showed that treatment group did not predict cocarriage between patients and their close contacts (P > .05 for each gene).
INTERPRETATION
Although levels of erm(B) were higher in those receiving long-term macrolide therapy and evidence of gene cocarriage with close contacts was found, no evidence was found that macrolide use increased the onward transmission risk to their close contacts. This study therefore addresses concerns that long-term macrolide therapy could promote the dissemination of transmissible macrolide resistance.
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Humans; Macrolides; Oropharynx
PubMed: 35122749
DOI: 10.1016/j.chest.2022.01.045 -
The Journal of Biological Chemistry Jun 2024Antimicrobial resistance poses a serious threat to human health worldwide and its incidence continues to increase owing to the overuse of antibiotics and other factors....
Antimicrobial resistance poses a serious threat to human health worldwide and its incidence continues to increase owing to the overuse of antibiotics and other factors. Macrolide antibiotics such as erythromycin (EM) have immunomodulatory effects in addition to their antibacterial activity. Long-term, low-dose administration of macrolides has shown clinical benefits in treating non-infectious inflammatory respiratory diseases. However, this practice may also increase the emergence of drug-resistant bacteria. In this study, we synthesized a series of EM derivatives, and screened them for two criteria: (i) lack of antibacterial activity and (ii) ability to suppress tumor necrosis factor-α (TNF-α) production in THP-1 cells stimulated with lipopolysaccharide. Among the 37 synthesized derivatives, we identified a novel 12-membered ring macrolide EM982 that lacked antibacterial activity against Staphylococcus aureus and suppressed the production of TNF-α and other cytokines. The effects of EM982 on Toll-like receptor 4 (TLR4) signaling were analyzed using a reporter assay and Western blotting. The reporter assay showed that EM982 suppressed the activation of transcription factors, NF-κB and/or activator protein 1 (AP-1), in HEK293 cells expressing human TLR4. Western blotting showed that EM982 inhibited the phosphorylation of both IκB kinase (IKK) β and IκBα, which function upstream of NF-κB, whereas it did not affect the phosphorylation of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and c-Jun N-terminal kinase, which act upstream of AP-1. These results suggest that EM982 suppresses cytokine production by inhibiting phosphorylation of IKKβ and IκBα, resulting in the inactivation of NF-κB.
Topics: Humans; I-kappa B Kinase; Phosphorylation; NF-KappaB Inhibitor alpha; Cytokines; Erythromycin; THP-1 Cells; Tumor Necrosis Factor-alpha; Anti-Bacterial Agents; Macrolides; NF-kappa B; Signal Transduction; Staphylococcus aureus; Toll-Like Receptor 4
PubMed: 38762177
DOI: 10.1016/j.jbc.2024.107384 -
International Journal of Nanomedicine 2023Macrolide drugs are among the broad-spectrum antibiotics that are considered as "miracle drugs" against infectious diseases that lead to higher morbidity and mortality... (Review)
Review
Macrolide drugs are among the broad-spectrum antibiotics that are considered as "miracle drugs" against infectious diseases that lead to higher morbidity and mortality rates. Nevertheless, their effectiveness is currently at risk owing to the presence of devastating, antimicrobial-resistant microbes. In view of this challenge, nanotechnology-driven innovations are currently being anticipated for promising approaches to overcome antimicrobial resistance. Nowadays, various nanostructures are being developed for the delivery of antimicrobials to counter drug-resistant microbial strains through different mechanisms. Metallic nanoparticle-based delivery of macrolides, particularly using silver and gold nanoparticles (AgNPs & AuNPs), demonstrated a promising outcome with worthy stability, oxidation resistance, and biocompatibility. Similarly, macrolide-conjugated magnetic NPs resulted in an augmented antimicrobial activity and reduced bacterial cell viability against resistant microbes. Liposomal delivery of macrolides also showed favorable synergistic antimicrobial activities in vitro against resistant strains. Loading macrolide drugs into various polymeric nanomaterials resulted in an enhanced zone of inhibition. Intercalated nanomaterials also conveyed an outstanding macrolide delivery characteristic with efficient targeting and controlled drug release against infectious microbes. This review abridges several nano-based delivery approaches for macrolide drugs along with their recent achievements, challenges, and future perspectives.
Topics: Gold; Macrolides; Metal Nanoparticles; Anti-Bacterial Agents; Nanostructures
PubMed: 37732155
DOI: 10.2147/IJN.S418588 -
Respiratory Investigation Sep 2015Community-acquired pneumonia (CAP) is a leading cause of death from an infectious cause worldwide. Guideline-concordant antibiotic therapy initiated in a timely manner... (Review)
Review
Community-acquired pneumonia (CAP) is a leading cause of death from an infectious cause worldwide. Guideline-concordant antibiotic therapy initiated in a timely manner is associated with improved treatment responses and patient outcomes. In the post-antibiotic era, much of the morbidity and mortality of CAP is as a result of the interaction between bacterial virulence factors and host immune responses. In patients with severe CAP, or who are critically ill, there is a lot of emerging observational evidence demonstrating improved survival rates when treatment using combination therapy with a β-lactam and a macrolide is initiated, as compared to other antibiotic regimes without a macrolide. Macrolides in combination with a β-lactam antibiotic provide broader coverage for the atypical organisms implicated in CAP, and may contribute to antibacterial synergism. However, it has been postulated that the documented immunomodulatory effects of macrolides are the primary mechanism for improved patient outcomes through attenuation of bacterial virulence factors and host systemic inflammatory responses. Despite concerns regarding the limitations of observational evidence and the lack of confirmatory randomized controlled trials, the potential magnitude of mortality benefits estimated at 20-50% cannot be overlooked. In light of recent data from a number of trials showing that combination treatment with a macrolide and a suitable second agent is justified in all patients with severe CAP, such treatment should be obligatory for those admitted to an intensive care setting.
Topics: Anti-Bacterial Agents; Community-Acquired Infections; Drug Therapy, Combination; Host-Pathogen Interactions; Humans; Immunomodulation; Macrolides; Pneumonia, Bacterial; Randomized Controlled Trials as Topic; Severity of Illness Index; beta-Lactams
PubMed: 26344609
DOI: 10.1016/j.resinv.2015.05.003