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Organic Letters Oct 2022The first asymmetric total synthesis and validation of the structural assignment of -thiomethyllooekeyolide A () is described, which features a Shiina macrolactonization...
The first asymmetric total synthesis and validation of the structural assignment of -thiomethyllooekeyolide A () is described, which features a Shiina macrolactonization and a late-stage pyran-hemiketal formation. The eight stereogenic centers of the C16-polyketide chain were installed by sequential aldol and crotylation reactions.
Topics: Macrolides; Pyrans; Stereoisomerism
PubMed: 36150127
DOI: 10.1021/acs.orglett.2c02412 -
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 -
Nature Communications Jul 2023Antibiotic resistance ABC-Fs (ARE ABC-Fs) are translation factors that provide resistance against clinically important ribosome-targeting antibiotics which are...
Antibiotic resistance ABC-Fs (ARE ABC-Fs) are translation factors that provide resistance against clinically important ribosome-targeting antibiotics which are proliferating among pathogens. Here, we combine genetic and structural approaches to determine the regulation of streptococcal ARE ABC-F gene msrD in response to macrolide exposure. We show that binding of cladinose-containing macrolides to the ribosome prompts insertion of the leader peptide MsrDL into a crevice of the ribosomal exit tunnel, which is conserved throughout bacteria and eukaryotes. This leads to a local rearrangement of the 23 S rRNA that prevents peptide bond formation and accommodation of release factors. The stalled ribosome obstructs the formation of a Rho-independent terminator structure that prevents msrD transcriptional attenuation. Erythromycin induction of msrD expression via MsrDL, is suppressed by ectopic expression of mrsD, but not by mutants which do not provide antibiotic resistance, showing correlation between MsrD function in antibiotic resistance and its action on this stalled complex.
Topics: Humans; Anti-Bacterial Agents; Drug Resistance, Bacterial; Macrolides; Abducens Nerve Diseases; Accommodation, Ocular
PubMed: 37393329
DOI: 10.1038/s41467-023-39553-8 -
BMC Nephrology Nov 2022Proton pump inhibitors (PPIs) are widely used for the treatment of gastrointestinal disorders such as peptic ulcer disease and dyspepsia. However, several studies have...
BACKGROUND
Proton pump inhibitors (PPIs) are widely used for the treatment of gastrointestinal disorders such as peptic ulcer disease and dyspepsia. However, several studies have suggested that PPI use increases the risk of acute kidney injury (AKI). PPIs are often concomitantly used with antibiotics, such as macrolides and penicillins for Helicobacter pylori eradication. Although macrolide antibiotics are considered to have relatively low nephrotoxicity, they are well known to increase the risk of AKI due to drug-drug interactions. In this study, we aimed to investigate the association between PPI use and the development of AKI. We also evaluated the effect of concomitant use of PPIs and macrolide antibiotics on the risk of AKI.
METHODS
This self-controlled case series study was conducted using electronic medical records at Kyoto University Hospital. We identified patients who were prescribed at least one PPI and macrolide antibiotic between January 2014 and December 2019 and underwent blood examinations at least once a year. An adjusted incident rate ratio (aIRR) of AKI with PPI use or concomitant use macrolide antibiotics with PPIs was estimated using a conditional Poisson regression model controlled for the estimated glomerular filtration rate at the beginning of observation and use of potentially nephrotoxic antibiotics.
RESULTS
Of the 3,685 individuals who received PPIs and macrolide antibiotics, 766 patients with episodes of stage 1 or higher AKI were identified. Any stage of AKI was associated with PPI use (aIRR, 1.80 (95% confidence interval (CI) 1.60 to 2.04)). Stage 2 or higher AKI was observed in 279 cases, with an estimated aIRR of 2.01 (95% CI 1.57 to 2.58, for PPI use). For the period of concomitant use of macrolide antibiotics with PPIs compared with the period of PPIs alone, an aIRR of stage 1 or higher AKI was estimated as 0.82 (95% CI 0.60 to 1.13).
CONCLUSIONS
Our findings added epidemiological information for the association between PPI use and an increased risk of stage 1 or higher AKI. However, we did not detect an association between the concomitant use of macrolide antibiotics and an increased risk of AKI in PPI users.
Topics: Humans; Proton Pump Inhibitors; Macrolides; Acute Kidney Injury; Research Design; Anti-Bacterial Agents
PubMed: 36451129
DOI: 10.1186/s12882-022-03008-x -
Journal of the American Chemical Society Sep 2020Lankacidins are a class of polyketide natural products isolated from that show promising antimicrobial activity. Owing to their complex molecular architectures and...
Lankacidins are a class of polyketide natural products isolated from that show promising antimicrobial activity. Owing to their complex molecular architectures and chemical instability, structural assignment and derivatization of lankacidins are challenging tasks. Herein we describe three fully synthetic approaches to lankacidins that enable access to new structural variability within the class. We use these routes to systematically generate stereochemical derivatives of both cyclic and acyclic lankacidins. Additionally, we access a new series of lankacidins bearing a methyl group at the C4 position, a modification intended to increase chemical stability. In the course of this work, we discovered that the reported structures for two natural products of the lankacidin class were incorrect, and we determine the correct structures of 2,18--lankacidinol B and -lankacidinol. We also evaluate the ability of several - and -lankacidins to inhibit the growth of bacteria and to inhibit translation in vitro. This work grants insight into the rich chemical complexity of this class of antibiotics and provides an avenue for further structural derivatization.
Topics: Anti-Bacterial Agents; Bacillus subtilis; Crystallography, X-Ray; Macrolides; Microbial Sensitivity Tests; Micrococcus; Models, Molecular; Molecular Structure; Staphylococcus aureus; Stereoisomerism; Streptomyces
PubMed: 32786797
DOI: 10.1021/jacs.0c06648 -
Microbiology Spectrum Dec 2022Our previous study identified that the Mycobacterium abscessus subsp. T28 sequevar does not fully represent inducible macrolide resistance. Thus, we initiated a...
Our previous study identified that the Mycobacterium abscessus subsp. T28 sequevar does not fully represent inducible macrolide resistance. Thus, we initiated a correlation study between genotypes and phenotypes. In total, 75 isolates from patients with skin and soft tissue infections were enrolled in the study. These strains were tested against 11 antimycobacterial agents using Sensitire RAPMYCO plates and the CLSI-recommended broth microdilution method. In order to analyze (41) and partial , , , and genes, bacterial genomic DNA was extracted from bacteria. The MEGA X software was used for phylogenetic analyses. The most active agents against most M. abscessus species were amikacin and tigecycline. Clarithromycin was effective toward M. abscessus subsp. and nearly all M. abscessus subsp. C28 sequevars. Two varieties of M. abscessus subsp. T28 sequevars did not represent inducible macrolide resistance. Most M. abscessus species showed intermediate susceptibility to cefoxitin and imipenem. Six additional agents were less effective against M. abscessus species. Following phylogenetic analyses, two outliers of M. abscessus subsp. T28 sequevars seem to represent no inducible macrolide resistance. In addition, we discovered genetic mosaicism of , , and in M. abscessus species was common. T28 sequevars of M. abscessus subsp. do not fully represent inducible macrolide resistance. The outlier of (41) phylogeny of the M. abscessus subsp. T28 sequevar is possibly due to macrolide susceptibility. Evaluation of the antimicrobial susceptibility of M. abscessus species is a reliable tool for assisting physicians in selecting the most effective antimycobacterial agent(s). Macrolides are the mainstays of the antimycobacterial regimens against Mycobacterium abscessus species (formerly Mycobacterium abscessus complex). (41) confers inducible macrolide resistance for M. abscessus subsp. strains, and the majority of M. abscessus subsp. T28 sequevars. Furthermore, the acquired macrolide resistance of M. abscessus species is due to a point mutation in . However, not all M. abscessus subsp. T28 sequevars have inducible macrolide resistance. Exploration of the mechanism of macrolide resistance requires an understanding of genetic diversity. The genetic mosaicism of the (41), , , and genes within three subspecies of M. abscessus species is not uncommon. The T28 sequevar of (41) confers inducible macrolide resistance to the genetic mosaic strain. The development of new anti-M. abscessus species infection overcoming inducible macrolide resistance and/or acquired macrolide resistance is a crucial issue.
Topics: Humans; Anti-Bacterial Agents; Mycobacterium abscessus; Phylogeny; Macrolides; Drug Resistance, Bacterial; Mycobacterium; Mycobacterium Infections, Nontuberculous; Point Mutation; Protein Synthesis Inhibitors; Microbial Sensitivity Tests
PubMed: 36416559
DOI: 10.1128/spectrum.02749-22 -
APMIS : Acta Pathologica,... Dec 2021This study aims to investigate prevalence of Mycoplasma genitalium and macrolide resistance-associated mutations and coinfection with other sexually transmitted bacteria...
This study aims to investigate prevalence of Mycoplasma genitalium and macrolide resistance-associated mutations and coinfection with other sexually transmitted bacteria in Southern Jutland, Denmark, where this information is very limited. Urinary samples from patients suspected of sexually transmitted bacterial infections collected at primary healthcare facilities in Southern Jutland are routinely tested for Chlamydia trachomatis and Neisseria gonorrhoeae. 601 of these samples were analysed with SpeeDx MG+23S reagents, which can detect M. genitalium and macrolide resistance-mediating mutations in the 23S rRNA gene. Moreover, 147 C. trachomatis positive urinary samples from routine test were also analysed with the PCR assay to detect M. genitalium. 72 out of 601 samples were detected positive for C. trachomatis (12%), five samples (0.83%) positive for N. gonorrhoeae and 25 samples positive for M. genitalium (4.2%). 14 of the 25 M. genitalium samples were detected having 23S rRNA gene mutations associated with macrolide resistance (56%). 25 of 147 C. trachomatis positive samples were tested positive for M. genitalium (17%) and two of them were positive for M. genitalium and N. gonorrhoeae (1.4%). The high prevalence of M. genitalium and macrolide resistance-associated mutation and the coinfection with C. trachomatis in the region suggesting that M. genitalium testing should be included in routine sexually transmitted infection screening.
Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Chlamydia Infections; Chlamydia trachomatis; Coinfection; Denmark; Drug Resistance, Bacterial; Female; Humans; Macrolides; Male; Middle Aged; Mutation; Mycoplasma Infections; Mycoplasma genitalium; Prevalence; Young Adult
PubMed: 34580906
DOI: 10.1111/apm.13174 -
Emerging Infectious Diseases Oct 2020Macrolide-resistant Bordetella pertussis emerged in Vietnam during 2016-2017. Direct analyses of swab samples from 10 patients with pertussis revealed a...
Macrolide-resistant Bordetella pertussis emerged in Vietnam during 2016-2017. Direct analyses of swab samples from 10 patients with pertussis revealed a macrolide-resistant mutation, A2047G, in the 23S rRNA. We identified the MT104 genotype of macrolide-resistant B. pertussis (which is prevalent in mainland China) and its variants in these patients.
Topics: Anti-Bacterial Agents; Bordetella pertussis; China; Drug Resistance, Bacterial; Erythromycin; Humans; Macrolides; RNA, Ribosomal, 23S; Vietnam
PubMed: 32946738
DOI: 10.3201/eid2610.201035 -
Journal of Natural Products Dec 2022A series of novel macrolides were discovered from the culture supernatant of the rare soil actinobacteria and named dactylosporolides A-C. The structure and absolute...
A series of novel macrolides were discovered from the culture supernatant of the rare soil actinobacteria and named dactylosporolides A-C. The structure and absolute configuration of these dactylosporolides were defined using a combination of NMR structural elucidation and analysis of the dactylosporolide biosynthetic gene cluster. Together these data revealed dactylosporolides to be composed of a central 22-membered macrolactone with an internal hemiketal ring and a protruding ketide tail that were (poly)glycosylated at two distal parts. While bearing no antibiotic activity, these dactylosporolides displayed activity against 3D7.
Topics: Macrolides; Micromonosporaceae; Actinobacteria; Glycosylation; Anti-Bacterial Agents
PubMed: 36512509
DOI: 10.1021/acs.jnatprod.2c00484 -
Molecules (Basel, Switzerland) Oct 2019Antimicrobial resistance has been seriously threatening human health, and discovering new antimicrobial agents from the natural resource is still an important pathway... (Review)
Review
Antimicrobial resistance has been seriously threatening human health, and discovering new antimicrobial agents from the natural resource is still an important pathway among various strategies to prevent resistance. Guanidine-containing polyhydroxyl macrolides, containing a polyhydroxyl lactone ring and a guanidyl side chain, can be produced by many actinomycetes and have been proved to possess many bioactivities, especially broad-spectrum antibacterial and antifungal activities. To explore the potential of these compounds to be developed into new antimicrobial agents, a review on their structural diversities, spectroscopic characterizations, bioactivities, acute toxicities, antimicrobial mechanisms, and the structure-activity relationship was first performed based on the summaries and analyses of related publications from 1959 to 2019. A total of 63 guanidine-containing polyhydroxyl macrolides were reported, including 46 prototype compounds isolated from 33 marine and terrestrial actinomycetes and 17 structural derivatives. Combining with their antimicrobial mechanisms, structure-activity relationship analyses indicated that the terminal guanidine group and lactone ring of these compounds are vital for their antibacterial and antifungal activities. Further, based on their bioactivities and toxicity analyses, the discovery of guanidyl side-chain targeting to lipoteichoic acid of indicated that these compounds have a great potency to be developed into antimicrobial and anti-inflammatory drugs.
Topics: Guanidine; Macrolides; Phylogeny; Spectrum Analysis; Structure-Activity Relationship; Toxicity Tests, Acute
PubMed: 31671653
DOI: 10.3390/molecules24213913