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13 recordsLinked to original sources
PubMed2026

Development and validation of a novel LC-MS/MS method for simultaneous quantification of fidaxomicin and metabolite (OP-1118) from feces for gut pharmacobiome studies.

Fidaxomicin is a first-line antibiotic for treating Clostridioides difficile infection. While it has low systemic absorption and reaches high colonic concentrations, it is hydrolyzed to a less active metabolite, OP-1118. Few studies have completely described critical experimental details of liquid chromatography-tandem mass spectrometry (LC-MS/MS) for quantifying fecal fidaxomicin and OP-1118. This study developed and validated a simple, fast, and sensitive LC-MS/MS method to quantify fidaxomicin and OP-1118 in human and mouse feces. This method simplified fecal sample preparation without the use of solid phase extraction and optimized LC-MS/MS parameters. A broad working range (0.3-1000 ng/ml) in both diluted human and murine fecal matrices was achieved with good intra- and inter-day accuracy (93-107%), precision (1-7%), and recovery (70-105%) as well as little IS-normalized matrix effects. This method was utilized to quantify fidaxomicin and OP-1118 in human and murine fecal samples. This novel method was simple, fast, sensitive, and accurate in analyzing fecal fidaxomicin and OP-1118 and could be deployed to facilitate gut pharmacobiome research.

Feces↗
PubMed2026

Dichalcogenide Fidaxomicin Derivatives to Probe Thiol-Mediated Uptake into Bacteria.

The natural product fidaxomicin (Fdx) is a narrow-spectrum antibiotic clinically prescribed for the treatment of Clostrodioides difficile infections. However, limited cellular uptake reduces its therapeutic potential, particularly against Gram-negative bacteria and mycobacteria. In this study, we investigated Thiol-Mediated Uptake (TMU) to promote the delivery of Fdx into bacterial cells. We synthesized a library of Fdx derivatives bearing cyclic dichalcogenide moieties and evaluated their antimicrobial properties against C. difficile and Mycobacterium tuberculosis, respectively. Remarkably, the synthetic Fdx derivatives retained strong levels of antibacterial activity, and the disulfide-containing analogs outperformed their all-carbon control counterparts in many instances. We then developed a systematic study to investigate the mechanistic impact of the introduced disulfide functionalities by conducting experiments with TMU inhibitors and quantifying intracellular accumulation in Mycobacterium bovis BCG, a model organism for M. tuberculosis, via LC-MS/MS. While complete disentanglement of the factors influencing activity was not feasible, features such as compound stability and lipophilicity were identified as significant contributors. Overall, the superior performance of disulfide analogs suggests that differences in cellular entry or intracellular processing, potentially related to TMU, are involved. This work highlights that TMU remains a viable approach for modulating the uptake of therapeutic agents into bacterial cells.

Sulfhydryl Compounds↗
PubMed2026

Genome-sequencing-based benchmarking of antimicrobial resistance, treatment outcomes and healthcare transmission events for Clostridioides difficile infection in Australian hospitals.

BACKGROUND: Clostridioides difficile infection (CDI) remains a priority for infection prevention and control in health care, particularly with the emergence of hypervirulent strains and antimicrobial resistance (AMR). AIM: To characterize the genomic epidemiology and AMR profiles of culture-confirmed CDI cases within tertiary hospitals in Australia. METHODS: A total of 155 C. difficile isolates from 142 patients with CDI diagnosed in four hospitals between 2023 and 2025 were studied. Data collected included patient demographics, severity of infection, antibiotic treatment and clinical outcomes at 8 weeks. Phenotypic susceptibility to vancomycin, fidaxomicin, metronidazole, moxifloxacin, meropenem, tetracycline and rifaximin were determined by agar dilution. Isolates underwent whole-genome sequencing (WGS) for genotyping and resistome assessment. FINDINGS: WGS differentiated 39 distinct sequence types among CDI isolates across different healthcare services. In total, 100 isolates were singletons and 55 (35% clustering rate) isolates were considered to be genomically related (difference of two or fewer single-nucleotide polymorphisms). Of these, 12 patients (8.5%) with close hospital contact formed six epidemiologically linked clusters. Phenotypic susceptibility results were obtained for 134 (86.4%) CDI isolates. There was no phenotypic resistance to vancomycin [minimum inhibitory concentration required to inhibit the growth of 90% of isolates (MIC90) 1 mg/L], metronidazole (MIC90 0.5 mg/L) or fidaxomicin (MIC90 0.5 mg/L). There was no association in the study cohort between the presence of resistance genes or reduced phenotypic susceptibility and CDI recurrence. CONCLUSION: Genomic analysis of C. difficile isolates did not identify any outbreaks or an association between the sequence type or presence of a resistance gene and clinical outcomes. High-resolution characterization and identification of antibiotic resistance, CDI clinical relapse and recent transmission offered by genome sequencing can provide important benchmarks for hospital infection control.

Antibiotic resistance↗
PubMed1996

A method for the selective isolation of Myxococcus directly from soil.

A new method is described for the selective isolation of species of Myxococcus directly from soil by dilution plating. The method involves suppression of competing microorganisms with antibiotics combined with air drying and wet heat treatment of soils. Fungi were eliminated by supplementing the plating medium with cycloheximide and nystatin. Non-sporulating bacteria were controlled by air drying soils and then heating aqueous soil dilutions for 10 min at 56 degrees C. The predominant sporulating bacteria in soil, Streptomyces and Bacillus, were suppressed by adding either tiacumicin B, ristocetin or vancomycin to the medium. Swarming of Myxococcus colonies was controlled with a casein digest-yeast extract plating medium (CY-C10 agar). Ultrasound treatment of soil suspensions gave the highest number of Myxococcus colonies in the soils studied, but these cultures could be recovered without ultrasound. Strains of Myxococcus fulvus, M. xanthus, M. coralloides, M. stipitatus and M. virescens were isolated from soil using this technique. Soils examined yielded one or two Myxococcus species per sample.

Aminoglycosides↗
PubMed1991

In vitro and in vivo evaluation of tiacumicins B and C against Clostridium difficile.

Tiacumicins B and C are members of a novel group of 18-membered macrolide antibiotics with in vitro activity against Clostridium difficile. The MICs against 15 strains of C. difficile were 0.12 to 0.25 microgram/ml for tiacumicin B, 0.25 to 1 microgram/ml for tiacumicin C, and 0.5 to 1 microgram/ml for vancomycin. The resistance frequency for both compounds against C. difficile was less than 2.8 x 10(-8) at four and eight times the MIC. The in vivo activities of the tiacumicins against two strains of C. difficile were compared with that of vancomycin in a hamster model of antibiotic-associated colitis. Oral therapy with 0.2, 1, or 5 mg of tiacumicin B or C per kg of body weight protected 100% of clindamycin-treated hamsters exposed to C. difficile ATCC 9689. Oral treatment with identical doses of vancomycin produced a prolonged, dose-dependent survival of hamsters, but it did not prevent the development of fatal colitis at doses of up to 5 mg/kg. When clindamycin-treated animals were exposed to another strain of C. difficile, both tiacumicin B and vancomycin were protective at 5 mg/kg, but not at lower doses. Tiacumicin C was not tested in vivo against the second strain of C. difficile. No tiacumicin B or C was detected in the sera of hamsters treated with single oral doses of 25 mg/kg, while antibiotic levels in the ceca of these hamsters reached 248 micrograms/ml and 285 mg/ml for tiacumicins B and C, respectively. The tiacumicins demonstrated in vitro and in vivo potencies against C. difficile and achieved high concentrations in the cecum, but not the serum, of hamsters after oral administration.

Aminoglycosides↗
PubMed1981

Transcriptional inhibition and production of guanosine polyphosphates in Bacillus subtilis.

When exponentially growing cells of Bacillus subtilis were treated with rifampin or lipiarmycin, both inhibitors of the initiation of ribonucleic acid synthesis, large amounts of (p)ppGpp accumulated. This accumulation appears to be independent of the ribosome-dependent stringent factor reaction because both relA and relC mutants responded in a manner similar to that of the wild type. The possibility that ribonucleic acid polymerase is directly involved in (p)ppGpp metabolism is discussed.

Aminoglycosides↗
PubMed1980

Inhibition by lipiarmycin of bacteriophage growth in Bacillus subtilis.

We have used lipiarmycin, a specific inhibitor of initiation of transcription, to study the role of host RNA polymerase in the transcription programs of various phages of Bacillus subtilis. Unlike rifampin, lipiarmycin preferentially inhibits transcription dependent on the sigma subunit of RNA polymerase because it inactivates holoenzyme at a much greater rate than it does core enzyme. With phage SP01, addition of lipiarmycin at a middle-to-late time of infection did not inhibit phage production even though phage production was sensitive to addition of rifampin at that time. This result is consistent with the notion that unmodified host RNA polymerase holoenzyme becomes dispensable after transcription of early classes of SP01 genes, even though host core enzyme is required for synthesis of all classes of phage RNA. SP01-modified forms of RNA polymerase, which lack sigma subunit but contain phage-coded polypeptides and are able to transcribe middle and late genes, were resistant to lipiarmycin in vitro. For phage phi 105, phage development was sensitive to both lipiarmycin and rifampin in wild-type cells and resistant to both drugs in resistant mutant cells, leading to the conclusion that the activity of host holoenzyme was required for phage RNA synthesis. Growth of phage PBS2, which was resistant to rifampin, was sensitive to the addition of lipiarmycin at early times of infection of a wild-type host strain. In a lipiarmycin-resistant mutant host, PBS2 growth was resistant to lipiarmycin. This result suggests that host holoenzyme plays a previously unanticipated role in transcription of PBS2 genes.

Aminoglycosides↗
PubMed1983

Structural studies on lipiarmycin. I. Characterization by 1H and 13C NMR spectroscopy and isolation of methyl 2-O-methyl-4-O-homodichloroorsellinate-beta-rhamnoside.

1H and 13C NMR spectral studies of lipiarmycin in CDCl3 and in pyridine-d5 provided evidence for the six partial structures I approximately VI and the two sugar units 1 and 2. Acid methanolysis led to the isolation of methyl 2-O-methyl-4-O-homodichloroorsellinate-beta-rhamnoside, whose structure was determined by spectroscopic methods.

Aminoglycosides↗
PubMed1986

Clostomicins, new antibiotics produced by Micromonospora echinospora subsp. armeniaca subsp. nov. I. Production, isolation, and physico-chemical and biological properties.

A soil isolate named as Micromonospora echinospora subsp. armeniaca subsp. nov. KMR-593 was found to produce at least five related antibiotics, clostomicins, active against Gram-positive bacteria including anaerobes. From the physico-chemical properties, one of these components was identified with lipiarmycin and others were found to be new antibiotics. Each component includes two chlorine atoms and the molecular weights of A and B2, C, and D are 1,058, 1,042 and 1,056, respectively. The structural differences were characterized by NMR analyses.

Aminoglycosides↗
PubMed1987

Tiacumicins, a novel complex of 18-membered macrolide antibiotics. I. Taxonomy, fermentation and antibacterial activity.

A complex of 18-membered macrolide antibiotics has been discovered in the fermentation broth of strain AB718C-41. The producing culture, isolated from a soil sample collected in Hamden, Connecticut, was identified as a strain of Dactylosporangium aurantiacum and was designated D. aurantiacum subsp. hamdenesis subsp. nov. The antibiotic complex was produced in a New Brunswick 150-liter fermentor using a medium consisting of glucose, soybean oil, soybean flour, beef extract and inorganic salts. Several of the antibiotics were active against sensitive and multiple antibiotic-resistant strains of pathogenic Gram-positive bacteria.

Actinomycetales↗
PubMed1987

Tiacumicins, a novel complex of 18-membered macrolides. II. Isolation and structure determination.

A novel complex of Gram-positive antibiotics has been isolated from the fermentation broth and mycelium of Dactylosporangium aurantiacum subsp. hamdenesis subsp. nov. The structures of these six compounds were deduced employing UV, MS, IR, and extensive 1D and 2D homonuclear and heteronuclear NMR experiments. Each component contained a highly unsaturated 18-membered macrolide ring. Components differed from one another by minor structural variations in the macrolide ring and by the number and esterification pattern of glycosidically bound sugars.

Actinomycetales↗
PubMed1988

Structure and biological activity of lipiarmycin B.

Actinoplanes deccanensis ATCC 21983, the producer of antibiotics lipiarmycin A3 and A4, furnished also a related antibiotic designated lipiarmycin B, active against Gram-positive bacteria, including anaerobes, and against Neisseria. The structures of the two major components, B3 and B4, were elucidated from their physico-chemical properties, 1H and 13C NMR spectra and fast atom bombardment mass spectra data in comparison with lipiarmycins A3 and A4.

Aminoglycosides↗