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The Lancet. Respiratory Medicine Apr 2024
Topics: Humans; Macrolides; Pneumonia; Anti-Bacterial Agents; Community-Acquired Infections
PubMed: 38184007
DOI: 10.1016/S2213-2600(23)00434-4 -
Journal of Cachexia, Sarcopenia and... Dec 2023Previous data from a 2-year randomized controlled trial (CRAD001ADE12) indicated that mammalian target of rapamycin (mTOR) inhibition by everolimus slowed cyst growth in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Previous data from a 2-year randomized controlled trial (CRAD001ADE12) indicated that mammalian target of rapamycin (mTOR) inhibition by everolimus slowed cyst growth in patients with autosomal-dominant polycystic kidney disease (ADPKD). During the trial, we noted body weight loss in some patients, particularly in women. We hypothesized that everolimus causes body weight reduction by reduced food intake and/or metabolic changes, which could lead to cachexia.
METHODS
Within a sub-analysis of the CRAD001ADE12 trial, body weight course was investigated regarding sex-specific differences in 433 adult ADPKD patients (everolimus, n = 215; placebo, n = 218). One hundred four out of 111 patients who participated in the clinical trial centre in Berlin were evaluated under everolimus/placebo therapy (on drug: everolimus, n = 48; placebo, n = 56) and after therapy (off drug: everolimus, n = 15; placebo, n = 18). Eating habits and nutrient/caloric intake were evaluated by validated questionnaires. Systemic and local metabolism was evaluated in four patients after an oral glucose load (OGL) by using calorimetry and adipose/muscle tissue microdialysis.
RESULTS
Within the 2-year CRAD001ADE12 trial, a significant body weight loss was observed in female patients on everolimus versus placebo (P = 0.0029). Data of the Berlin Cohort revealed that weight loss was greater in women on everolimus versus men (P < 0.01). After 9 months, women and men had lost 2.6 ± 3.8 and 0.8 ± 1.5 kg (P < 0.05) in body weight, respectively, and after 21 months, they had lost 4.1 ± 6.6 and 1.0 ± 3.3 kg (P < 0.05), respectively. On everolimus, caloric intake was significantly lower in women versus men (1510 ± 128 vs. 2264 ± 216 kcal/day, P < 0.05), caused mainly by a lower fat and protein intake in women versus men. Cognitive restraints, disinhibition and hunger remained unchanged. In a subgroup of patients resting metabolic rate was unchanged whereas OGL-induced thermogenesis was reduced (7 ± 2 vs. 11 ± 2 kcal, P < 0.05). Fasting and OGL-induced fat oxidation was increased (P < 0.05) on versus off everolimus. In adipose tissue, fasting lipolytic activity was increased, but lipolytic activity was inhibited similarly after the OGL on versus off everolimus, respectively. In skeletal muscle, postprandial glucose uptake and aerobic glycolysis was reduced in patients on everolimus.
CONCLUSIONS
mTOR inhibition by everolimus induces body weight reduction, specifically in female patients. This effect is possibly caused by a centrally mediated reduced food (fat and protein) intake and by centrally/peripherally mediated increased fat oxidation (systemic) and mobilization (adipose tissue). Glucose uptake and oxidation might be reduced in skeletal muscle. This could lead to cachexia and, possibly, muscle wasting. Therefore, our results have important implications for patients recieving immune-suppressive mTOR inhibition therapy.
Topics: Male; Adult; Humans; Female; Cachexia; Everolimus; Sirolimus; Polycystic Kidney, Autosomal Dominant; Body Weight; Weight Loss; TOR Serine-Threonine Kinases; Homeostasis; Glucose
PubMed: 37897143
DOI: 10.1002/jcsm.13352 -
Microbiology Spectrum Aug 2023We present two independent cases of recurrent multidrug-resistant Campylobacter jejuni infection in immunocompromised hosts and the clinical challenges encountered due...
We present two independent cases of recurrent multidrug-resistant Campylobacter jejuni infection in immunocompromised hosts and the clinical challenges encountered due to the development of high-level carbapenem resistance. The mechanisms associated with this unusual resistance for were characterized. Initial macrolide and carbapenem-susceptible strains acquired resistance to erythromycin (MIC > 256mg/L), ertapenem (MIC > 32mg/L), and meropenem (MIC > 32mg/L) during treatment. Carbapenem-resistant isolates developed an in-frame insertion resulting in an extra Asp residue in the major outer membrane protein PorA, within the extracellular loop L3 that connects β-strands 5 and 6 and forms a constriction zone involved in Ca binding. The isolates presenting the highest MIC to ertapenem exhibited an extra nonsynonymous mutation (G167A|Gly56Asp) at PorA's extracellular loop L1. Carbapenem susceptibility patterns suggest drug impermeability, related to either insertion and/or single nucleotide polymorphism (SNP) within A. Similar molecular events occurring in two independent cases support the association of these mechanisms with carbapenem resistance in Campylobacter spp.
Topics: Humans; Macrolides; Carbapenems; Campylobacter jejuni; Ertapenem; Drug Resistance, Bacterial; Anti-Bacterial Agents; Campylobacter Infections; Microbial Sensitivity Tests
PubMed: 37358443
DOI: 10.1128/spectrum.01070-23 -
Organic Letters Nov 2023A convergent route for the asymmetric total synthesis of antibacterial macrolide sorangiolide A has been developed for the first time. The key feature of this synthesis...
A convergent route for the asymmetric total synthesis of antibacterial macrolide sorangiolide A has been developed for the first time. The key feature of this synthesis includes Krische iridium-catalyzed -diastereoselective carbonyl crotylation, Crimmins acetate aldol, Yamaguchi esterification, Julia-Kocienski olefination, Horner-Wadsworth-Emmons olefination, and ring-closing metathesis. The origin of the low intensity of the C{H} NMR signals of the C1 and C2 centers of the natural product has been investigated, disclosing possible forms of existence for the natural product in the solution phase.
Topics: Macrolides; Stereoisomerism; Esterification; Anti-Bacterial Agents; Biological Products; Molecular Structure
PubMed: 37856450
DOI: 10.1021/acs.orglett.3c03066 -
Genes Apr 2024() poses a significant public health challenge due to its association with non-gonococcal urethritis (particularly in men) and antimicrobial resistance. However,...
() poses a significant public health challenge due to its association with non-gonococcal urethritis (particularly in men) and antimicrobial resistance. However, despite the prevalence of infections and the rise in resistance rates, routine testing and surveillance remain limited. This is the first study from Croatia that aimed to assess the prevalence and trends of resistance in strains isolated from male individuals by detecting macrolide and fluoroquinolone resistance genes. The study also aimed to explore the factors associated with resistance and changes in resistance patterns over time. Urine samples collected from male individuals in the Zagreb County and northwest region of Croatia between 2018 and 2023 were tested for with the use of molecular methods. Positive samples were subjected to DNA extraction and multiplex tandem polymerase chain reaction (MT-PCR) targeting genetic mutations associated with macrolide ( gene) and fluoroquinolone ( gene) resistance. Of the 8073 urine samples tested from 6480 male individuals (and following the exclusion of repeated specimens), we found that the prevalence of infection was 2.2%. Macrolide resistance was observed in 60.4% of strains, while fluoroquinolone resistance was found in 19.2%. Co-resistance to both antibiotics was present in 18.2% of cases. A statistically significant increase in fluoroquinolone resistance was noted over the study period ( = 0.010), but this was not evident for azithromycin resistance ( = 0.165). There were no statistically significant differences in resistance patterns between age groups, whereas re-testing of patients revealed dynamic changes in resistance profiles over time. The high burden of macrolide resistance and increasing fluoroquinolone resistance underscore the urgent need for comprehensive resistance testing and surveillance programs. The implementation of resistance-guided treatment strategies, along with enhanced access to molecular diagnostics, is pivotal for effectively managing infections.
Topics: Mycoplasma genitalium; Humans; Male; Fluoroquinolones; Croatia; Macrolides; Adult; Mycoplasma Infections; Anti-Bacterial Agents; Drug Resistance, Bacterial; Middle Aged; Young Adult; RNA, Ribosomal, 23S; Adolescent; Urethritis; Microbial Sensitivity Tests
PubMed: 38674404
DOI: 10.3390/genes15040470 -
The Journal of Organic Chemistry Aug 2023Enigmazole B () and four new analogues, -enigmazole B (), dehydroenigmazole B (), enigmimide B (), and enigmimide A (), were isolated from the marine sponge . Their...
Enigmazole B () and four new analogues, -enigmazole B (), dehydroenigmazole B (), enigmimide B (), and enigmimide A (), were isolated from the marine sponge . Their planar structures were elucidated by detailed NMR and MS data analyses, which established - to be oxazole-substituted 18-membered phosphomacrolides, while and were oxazole ring-opened congeners. The relative and absolute configurations in were determined by a combination of chemical transformations and spectroscopic analyses. Photooxidation of the oxazole moiety in gave enigmimide B (), thus establishing that has the same absolute configuration of . Enigmazole B () along with analogues and showed cytotoxicity against murine IC-2 mast cells with IC values of 3.6-7.0 μM. The enigmimides ( and ) and dephosphoenigmazoles did not show cytotoxicity (IC > 10 μM), implying that both the oxazole moiety and the phosphate group are necessary for the cytotoxicity of the enigmazole class macrolides.
Topics: Animals; Mice; Porifera; Macrolides; Oxazoles; Anti-Bacterial Agents; Molecular Structure
PubMed: 37471139
DOI: 10.1021/acs.joc.3c00963 -
Neuropharmacology Mar 2024Current evidence suggests that hyperactivated or impaired autophagy can lead to neuronal death. The effect of local anesthetics on painful diabetic neuropathy (PDN) and...
Current evidence suggests that hyperactivated or impaired autophagy can lead to neuronal death. The effect of local anesthetics on painful diabetic neuropathy (PDN) and the role of autophagy in the above pathological process remain unclear, warranting further studies. So, PDN models were established by assessing the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in leptin gene-mutation (db/db) mice. Wild type (WT) and PDN mice received intrathecal 0.75% bupivacaine or/with intraperitoneal drug treatment (rapamycin or bafilomycin A1). Subsequently, the PWT and PWL were measured to assess hyperalgesia at 6 h, 24 h, 30 h, and 48 h after intrathecal bupivacaine. Also, sensory nerve conduction velocity (SNCV) and motor nerve conduction velocity (MNCV) were measured before and 48 h after intrathecal bupivacaine treatment. The spinal cord tissue of L-L segments and serum were harvested to evaluate the change of autophagy, oxidative stress, oxidative injury, and apoptosis. We found that bupivacaine induced the activation of autophagy but did not affect the pain threshold, SNCV and MNCV in WT mice at predefined time points. Conversely, bupivacaine lowered autophagosome generation and degradation, slowed SNCV and aggravated spinal dorsal horn neuron oxidative injury and hyperalgesia in PDN mice. The autophagy activator (rapamycin) could decrease spinal dorsal horn neuron oxidative injury, alleviate the alterations in SNCV and hyperalgesia in bupivacaine-treated PDN mice. Meanwhile, the autophagy inhibitor (bafilomycin A1) could exacerbate spinal dorsal horn neuron oxidative injury, the alterations in SNCV and hyperalgesia in bupivacaine-treated PDN mice. Our results showed that bupivacaine could induce defective autophagy, slowed SNCV and aggravate spinal dorsal horn neuron oxidative injury and hyperalgesia in PDN mice. Restoring autophagy may represent a potential therapeutic approach against nerve injury in PDN patients with local anesthesia and analgesia.
Topics: Rats; Mice; Humans; Animals; Hyperalgesia; Rats, Sprague-Dawley; Diabetic Neuropathies; Bupivacaine; Sirolimus; Autophagy; Diabetes Mellitus; Macrolides
PubMed: 38104768
DOI: 10.1016/j.neuropharm.2023.109814 -
Biomedicine & Pharmacotherapy =... Sep 2023Maytansine is a pharmacologically active 19-membered ansamacrolide derived from various medicinal plants and microorganisms. Among the most studied pharmacological... (Review)
Review
Maytansine is a pharmacologically active 19-membered ansamacrolide derived from various medicinal plants and microorganisms. Among the most studied pharmacological activities of maytansine over the past few decades are anticancer and anti-bacterial effects. The anticancer mechanism of action is primarily mediated through interaction with the tubulin thereby inhibiting the assembly of microtubules. This ultimately leads to decreased stability of microtubule dynamics and cause cell cycle arrest, resulting in apoptosis. Despite its potent pharmacological effects, the therapeutic applications of maytansine in clinical medicine are quite limited due to its non-selective cytotoxicity. To overcome these limitations, several derivatives have been designed and developed mostly by modifying the parent structural skeleton of maytansine. These structural derivatives exhibit improved pharmacological activities as compared to maytansine. The present review provides a valuable insight into maytansine and its synthetic derivatives as anticancer agents.
Topics: Maytansine; Microtubules; Antineoplastic Agents; Tubulin
PubMed: 37364476
DOI: 10.1016/j.biopha.2023.115039 -
The American Journal of Tropical... Nov 2023Azithromycin mass drug administration decreases child mortality but also selects for antibiotic resistance. Herein, we evaluate macrolide resistance of nasopharyngeal... (Randomized Controlled Trial)
Randomized Controlled Trial
Temporal Trends in Phenotypic Macrolide and Nonmacrolide Resistance for Streptococcus pneumoniae Nasopharyngeal Samples Up to 36 Months after Mass Azithromycin Administration in a Cluster-Randomized Trial in Niger.
Azithromycin mass drug administration decreases child mortality but also selects for antibiotic resistance. Herein, we evaluate macrolide resistance of nasopharyngeal Streptococcus pneumoniae after azithromycin MDA. In a cluster-randomized trial, children 1-59 months received azithromycin or placebo biannually. Fifteen villages from each arm were randomly selected for antimicrobial resistance testing, and 10-15 randomly selected swabs from enrolled children at each village were processed for S. pneumoniae isolation and resistance testing. The primary prespecified outcome was macrolide resistance fraction for azithromycin versus placebo villages at 36 months. Secondary non-prespecified outcomes were comparisons of azithromycin and placebo for: 1) macrolide resistance at 12, 24, and 36 months; 2) nonmacrolide resistance at 36 months; and 3) suspected-erm mutation. At 36 months, 423 swabs were obtained and 322 grew S. pneumoniae, (azithromycin: 146/202, placebo: 176/221). Mean resistance prevalence was non-significantly higher in treatment than placebo (mixed-effects model: 14.6% vs. 8.9%; OR = 2.0, 95% CI: 0.99-3.97). However, when all time points were evaluated, macrolide resistance prevalence was significantly higher in the azithromycin group (β = 0.102, 95% CI: 0.04-0.167). For all nonmacrolides, resistance prevalence at 36 months was not different between the two groups. Azithromycin and placebo were not different for suspected-erm mutation prevalence. Macrolide resistance was higher in the azithromycin group over all time points, but not at 36 months. Although this suggests resistance may not continue to increase after biannual MDA, more studies are needed to clarify when MDA can safely decrease mortality and morbidity in lower- and middle-income countries.
Topics: Child; Humans; Infant; Azithromycin; Anti-Bacterial Agents; Macrolides; Streptococcus pneumoniae; Mass Drug Administration; Niger; Drug Resistance, Bacterial
PubMed: 37783458
DOI: 10.4269/ajtmh.23-0431 -
Communications Biology Jun 2024Macrolide antibiotics, pivotal in clinical therapeutics, are confronting resistance challenges mediated by enzymes like macrolide esterases, which are classified into...
Macrolide antibiotics, pivotal in clinical therapeutics, are confronting resistance challenges mediated by enzymes like macrolide esterases, which are classified into Ere-type and the less studied Est-type. In this study, we provide the biochemical confirmation of EstX, an Est-type macrolide esterase that initially identified as unknown protein in the 1980s. EstX is capable of hydrolyzing four 16-membered ring macrolides, encompassing both veterinary (tylosin, tidipirosin, and tilmicosin) and human-use (leucomycin A5) antibiotics. It uses typical catalytic triad (Asp233-His261-Ser102) from alpha/beta hydrolase superfamily for ester bond hydrolysis. Further genomic context analysis suggests that the dissemination of estX is likely facilitated by mobile genetic elements such as integrons and transposons. The global distribution study indicates that bacteria harboring the estX gene, predominantly pathogenic species like Escherichia coli, Salmonella enterica, and Klebsiella pneumoniae, are prevalent in 74 countries across 6 continents. Additionally, the emergence timeline of the estX gene suggests its proliferation may be linked to the overuse of macrolide antibiotics. The widespread prevalence and dissemination of Est-type macrolide esterase highlight an urgent need for enhanced monitoring and in-depth research, underlining its significance as an escalating public health issue.
Topics: Esterases; Anti-Bacterial Agents; Macrolides; Humans; Bacterial Proteins; Phylogeny; Hydrolases
PubMed: 38944651
DOI: 10.1038/s42003-024-06473-2