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At least 19 recordsLinked to original sources
PubMed1978

Polyene macrolide antibiotic cytotoxicity and membrane permeability alterations. I. Comparative effects of four classes of polyene macrolides on mammalian cells.

The relationship between polyene macrolide-induced early membrane damage and cytotoxicity in B1 (hamster), B82 (mouse), and RAG (mouse) cells has been investigated. Filipin (FIL) induced the greatest immediate damage, as monitored by 51Cr release, followed by mediocidin (MED), amphotericin B-deoxycholate (Fungizone) (FZ) and pimaricin (PIM). For long term effect, PIM was the least toxic followed by MED, FZ, and FIL as indicated by 24-hour survival, 72-hour viability, and growth rate of cells. In evaluating polyene macrolide-induced permeability alterations and cytotoxicity two types of interactions with mammalian cells were found: (1) cell toxicity at polyene macrolide levels not eliciting immediate membrane permeability changes; and (2) immediate membrane damage without long range toxicity.

Antibiotics, Antineoplastic↗
PubMed2026

Characterisation of Bordetella pertussis virulence and macrolide resistance in Australia by targeted culture-independent sequencing: a genomic epidemiology study.

BACKGROUND: Bordetella pertussis continues to circulate globally despite widespread vaccination, with a notable epidemic in 2024. Its resurgence is confounded by the emergence of pertactin-deficient, macrolide-resistant B pertussis strains in Asia and Europe, which are under-recognised by conventional diagnostics. We aimed to apply targeted culture-independent next-generation sequencing (tNGS) of respiratory specimens to improve global B pertussis diagnostic capability and genomic surveillance. METHODS: We did a nationwide genomic epidemiology study of B pertussis RT-PCR-positive respiratory specimens that were retrospectively and prospectively collected by diagnostic and public health laboratories in six of seven states and territories of Australia. Specimens underwent tNGS and macrolide-resistant B pertussis-specific PCR, and an opportunistic subset from New South Wales and Queensland were cultured for confirmatory susceptibility testing and whole-genome sequencing. Sequencing data were analysed for genome recovery, virulence profiles, and macrolide resistance mutations, and were compared with international macrolide-resistant B pertussis genomes and ancestral Australian genomes. The performance of the tNGS approach was assessed with logistic regression relative to RT-PCR cycle threshold values, and sensitivity and specificity values were calculated. FINDINGS: 255 respiratory specimens positive for B pertussis were included in the study. 64 (25%) were retrospectively collected between Jan 12, 2012, and Dec 31, 2023, and 191 (75%) were prospectively collected between Jan 1 and Oct 28, 2024. Of these 255 specimens, 148 (58%) yielded near-complete B pertussis genomes through tNGS. Seven co-circulating lineages of B pertussis were documented, including two associated with macrolide-resistance. Eight epidemiologically unrelated and geographically dispersed cases of macrolide-resistant B pertussis with a 23S rRNA 2037A→G mutation were identified by tNGS and confirmed by whole-genome sequencing. Three of these were further validated by phenotypic testing. The estimated prevalence of macrolide resistance among Australian cases positive for B pertussis was 4% (eight of 188). INTERPRETATION: tNGS can recover near-complete B pertussis genomes directly from clinical specimens, enabling identification of macrolide resistance mutations and high-resolution phylogenetic analysis. These findings show that tNGS complements PCR-based surveillance by providing genome-wide assessment of resistance, virulence, and genomic diversity in a single workflow. FUNDING: NSW Health Prevention Research Support Program.

Macrolides↗
PubMed2005

Molecular epidemiology of macrolide-resistant isolates of Streptococcus pneumoniae collected from blood and respiratory specimens in Norway.

Norway has a low prevalence of antimicrobial resistance, including macrolide-resistant Streptococcus pneumoniae (MRSP). In a nationwide surveillance program, a total of 2,200 S. pneumoniae isolates were collected from blood cultures and respiratory tract specimens. Macrolide resistance was detected in 2.7%. M-type macrolide resistance was found in 60% of resistant isolates, and these were mainly mef(A)-positive, serotype-14 invasive isolates. The erm(B)-encoded macrolide-lincosamide-streptogramin B (MLS(B)) type dominated among the noninvasive isolates. One strain had an A2058G mutation in the 23S rRNA gene. Coresistance to other antibiotics was seen in 96% of the MLS(B)-type isolates, whereas 92% of the M-type isolates were susceptible to other commonly used antimicrobial agents. Serotypes 14, 6B, and 19F accounted for 84% of the macrolide-resistant isolates, with serotype 14 alone accounting for 67% of the invasive isolates. A total of 29 different sequence types (STs) were detected by multilocus sequence typing. Twelve STs were previously reported international resistant clones, and 75% of the macrolide-resistant isolates had STs identical or closely related to these clones. Eleven isolates displayed 10 novel STs, and 7/11 of these "Norwegian strains" coexpressed MLS(B) and tetracycline resistance, indicating the presence of Tn1545. The invasive serotype-14 isolates were all classified as ST9 or single-locus variants of this clone. ST9 is a mef-positive M-type clone, commonly known as England(14)-9, reported from several European countries. These observations suggest that the import of major international MRSP clones and the local spread of Tn1545 are the major mechanisms involved in the evolution and dissemination of MRSP in Norway.

Drug Resistance, Bacterial↗
PubMed2026

Canalesolide A, a Structurally Unique Polyhydroxy Macrolide from the Marine Cyanobacterium Okeania sp. with Potent Antitrypanosomal Activity.

The discovery of structurally novel natural products remains central to expanding biologically relevant chemical space, particularly within underexplored marine metabolite classes. Herein, we report the discovery and complete structural elucidation of canalesolide A, a new polyhydroxylated macrolide isolated from the marine cyanobacterium Okeania sp. The compound was identified through an integrated workflow combining phenotypic screening against Trypanosoma brucei and LC-MS/MS-based molecular networking, enabling rapid prioritization of bioactive fractions and dereplication of known metabolite families. Spectroscopic analysis revealed that canalesolide A belongs to the bastimolide-related class of macrolides but exhibits a distinct structural architecture. Its structure was established by integrating ultrahigh-resolution NMR spectroscopy, empirical configurational analysis of polyol systems, targeted model compound synthesis, and controlled chemical degradation and derivatization. This combined strategy resolved stereochemical motifs that were inaccessible by direct analysis of the intact macrolide alone, providing a transferable approach for assigning densely oxygenated marine macrolides. Genome mining identified the putative biosynthetic gene cluster and proposed biosynthetic pathway for a bastimolide-related macrolide. Canalesolide A displays potent, low nanomolar antitrypanosomal activity against human-infective subspecies of T. brucei with rapid elimination of parasites within 1 h at 1 μM. Although moderate mammalian cytotoxicity was observed, preliminary in vivo efficacy/toxicity studies in infected mice suggest a narrow therapeutic window highlighting the need for improved selectivity. This study expands the structural and biosynthetic diversity of polyhydroxylated macrolides and establishes a generalizable framework for resolving stereochemically complex natural products.

Macrolides↗
PubMed1979

Polyene macrolide antibiotic cytotoxicity and membrane permeability alterations. II. Phenotypic expression in intraspecific and interspecific somatic cell hybrids.

Cytotoxicity and membrane permeability alterations induced by the polyene macrolide antibiotics filipin (FIL) and pimaricin (PIM) have been compared in parental intraspecific and interspecific somatic cell hybrids. B82 (mouse) and B1 (hamster) cells were found to be more resistant than RAG (mouse) parental cells to both polyene macrolides as indicated by 24-hour survival, 72-hour viability, and growth rate. Analysis of both intraspecific and interspecific somatic cell hybrids indicated that polyene macrolide resistance was being expressed even in the presence of the polyene macrolide-sensitive (RAG) genome. Where one of the two parental cell types is relatively polyene macrolide resistant, the use of specific polyene macrolides may prove efficacious as half-selective agents in cell hybridization.

Animals↗
PubMed1979

Hydroheptin: a water-soluble polyene macrolide. II. Chemical and biological properties.

Hydroheptin, a new polyene macrolide antifungal antibiotic, is co-produced with the antibiotic, chartreusin, by a strain of Streptomyces chartreusis designated as IMRU 3962 isolated in our laboratory. The unique water-solubility of this antibiotic at neutrality, revealing in aqueous solution molecular dispersion and an ultraviolet-visible absorption spectrum characteristic of an all-trans heptaene chromophore, clearly distinguishes it from all previously-described and naturally-occurring heptaene macrolides. The isolation and identification of the amino sugar, mycosamine (3-amino-3,6-dideoxy-D-mannose), in acid hydrolysates of hydroheptin and the absence of an aromatic amine upon retrograde alkaline dealdolization of the molecule certainly characterize the antibiotic as a member of the non-aromatic heptaene macrolide group. Chromatographic and countercurrent distribution studies likewise support its novelty. With little or no demonstrable activity against bacteria, hydroheptin as compared to other non-aromatic heptaene macrolides exhibits excellent but somewhat less activity against a wide variety of yeasts and fungi. Likewise, its parenteral toxicity appears to be less than that of other heptaene macrolides.

Animals↗
PubMed2025

Macrolide-resistant Mycoplasma pneumoniae resurgence in Chinese children in 2023: a longitudinal, cross-sectional, genomic epidemiology study.

BACKGROUND: After a prolonged period of low detection rates, Mycoplasma pneumoniae resurged in China, during September to November, 2023, raising global concern. This study aims to gain a better understanding of the genetic mechanisms underlying the 2023 increase in cases and the evolutionary dynamics of the epidemic populations, which has been previously hampered due to limited genomic data of this pathogen. METHODS: We sequenced 685 M pneumoniae isolates, including 248 isolates from 11 Chinese provinces and municipalities in 2023 and 437 isolates from Beijing (2013-22). By analysing these isolates and 436 publicly global sequences, we reconstructed the pathogen's evolutionary history using time-calibrated phylogenies and effective population size inference. We investigated potential genomic variations contributing to the 2023 resurgence through genome-wide association study and conducted phylogeographic analysis of the 2023 isolates across China. FINDINGS: Two macrolide-resistant epidemic clusters (T1-2-EC1 and T2-2-EC2) were responsible for the 2023 resurgence in China. Both clusters, having acquired the 23S ribosomal RNA A2063G mutation conferring macrolide resistance, emerged in approximately 1997 and 2014, respectively, and subsequently outcompeted their predecessor populations. This coincided with China's large-scale adoption of azithromycin for paediatric community-acquired pneumonia around the early 2000s. Aside from macrolide resistance, T1-2-EC1 independently acquired 17 clade-specific mutations and T2-2-EC2 four clade-specific mutations, which could further explain their increased competitiveness. Whole-genome analysis revealed no resurgence-specific mutations in the 2023 isolates. Phylogeographic analysis showed rapid mixing of T1-2-EC1 isolates between different sampled regions within China. INTERPRETATION: Our study provides evidence that the 2023 resurgence in China is a continuation of the pre-COVID epidemic, rather than emergence of novel variants. The high prevalence of macrolide resistance and rapid intranational spread emphasise the urgent need for enhanced global surveillance of this pathogen. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China for Key Programs of China Grants, and Beijing High-Level Public Health Technical Talent Project.

Humans↗
PubMed1979

Energy dependence and reversibility of membrane alterations induced by polyene macrolide antibiotics in Chlorella vulgaris.

The requirement of metabolic energy for the interaction of polyene macrolide antibiotics with eukaryotic organisms remains a controversial subject (for review see ref. 1) It has been claimed that the lethal binding of these antibiotics to the sterol target component of the hydrophobic core of the membrane, in accordance with the model of de Kruijff and Demel, is an energy-dependent process. When energy production is reduced by removal of all metabolisable substrates or by adding metabolic inhibitors, polyene binding and antifungal effects are also reduced. Metabolic energy may be required to maintain binding site accessibility or to move antibiotic molecules to the active site. The interaction is also restricted at low temperatures, possibly because of the reduced thermal mobilities of the groups concerned with antibiotic uptake. However, it should be emphasised that the interaction of polyene macrolides with artificial lipid membranes is a purely physicochemical process, although the type of permeability pathways induced are similar to those observed in natural membranes. Using Chlorella vulgaris as a model organism, we demonstrate here that the interaction of polyene macrolides with sensitive cells and the induction of lethal membrane permeability changes are energy-dependent processes or purely physicochemical phenomena, depending on the structure of the antibiotic used.

Anti-Bacterial Agents↗
PubMed1979

23S ribosomal ribonucleic acid of macrolide-producing streptomycetes contains methylated adenine.

Coresistance to macrolide, lincosamide, and streptogramin B-type (MLS) antibiotics by a common biochemical mechanism characterizes clinically resistant pathogens. Of 10 streptomycetes tested for resistance to macrolide, lincosamide, and streptogramin B-type antibiotics, only 1, Streptomyces erythreus, the organism used for production of erythromycin, was found resistant to all three classes; moreover, it was the only streptomycete in the series tested found to contain N6-dimethyladenine (m62A) in 23S ribosomal ribonucleic acid, the structural alteration of ribosomal ribonucleic acid associated with clinical resistance. Of the seven streptomycetes tested for the presence of m62A and N6-methyladenine (m6A), two, S. fradiae and S. cirratus, which produce the macrolide antibiotics tylosin and cirramycin, respectively, were found to contain m6A, but not m62A. The remaining strains tested, including strains which produce lincomycin and streptogramins, contained neither m6A nor m62A.

Adenine↗
PubMed1977

Mode of action of the protein, SP127, which enhances the activity of macrolide antibiotics against Pseudomonas aeruginosa.

Antibiotics, the activity of which enhanced against Pseudomonas aeruginosa by SP127, were restricted to the basic macrolide antibiotics such as erythromycin, maridomycin and oleandomycin, the neutral macrolide antibiotics such as lankamycin and lankacidin C, vancomycin and enramycin. Synergistic activity of SP127 with the above antibiotics was found against Pseudomonas aeruginosa and several strains of Escherichia coli, but not against Proteus vulgaris and macrolide-resistant Staphylococcus aureus. SP127 had extremely weak proteolytic but no lytic activity. From the isotopic experiments, the action of SP127 was partially attributed to the promotion of antibiotic penetration to cells of Pseudomonas aeruginosa.

Anti-Bacterial Agents↗
PubMed1979

Resistance of Mycoplasma pneumoniae to macrolide and analogous antibiotics.

1. The susceptibility of M. pneumoniae to antibiotics can be determined by the microtiter method. The adequate technique requires that the final volume of broth medium in a well is 0.2 ml and that the dilution is made after the parent solution of antibiotic in the test tube is dropped into a well every fifth wells. 2. M. pneumoniae was cultured on agar media containing two-fold concentrations of macrolide and analogous antibiotics, and the following results were obtained. 1) The growth of eight strains of M. pneumoniae on agar media containing two-fold concentrations of the antibiotics revealed that, in six strains, one CFU (colony forming unit) per 10(5) to 10(6) CFU of an inoculum dose was resistant to the antibiotics. 2) The MIC (minimum inhibitory concentration) of erythromycin for the subculture of thet strains of M. pneumoniae on agar media containing two-fold concentrations of the antibiotics revealed that, in six strains, one CFU (colony forming unit) per 10(5) to 10(6) CFU of an inoculum dose was resistant to the antibiotics. 2) The MIC (minimum inhibitory concentration) of erythromycin for the subculture of thet strains of M. pneumoniae on agar media containing two-fold concentrations of the antibiotics revealed that, in six strains, one CFU (colony forming unit) per 10(5) to 10(6) CFU of an inoculum dose was resistant to the antibiotics. 2) The MIC (minimum inhibitory concentration) of erythromycin for the subculture of the colony grown as an average of 0.5 to eight on agar media containing erythromycin in four strains was 0.1 to 1.6 micrograms/ml in some colonies, and 400 to 800 micrograms/ml in most colonies. The results disclosed that the broth culture contains a small number of mycoplasma cells with a definite, high degree of resistance to the antibiotics, but no cells with intermediate degrees of resistance. 3) The FH strain was made resistant to erythromycin, oleandomycin, midecamycin, acetylspiramycin, leucomycin, josamycin, tylosin, lincomycin, or clindamycin by subculture in broth medium from the colony grown at the highest concentrations of each of the antibiotics in agar media. The degree of the resistance developed was 16 to 128,000 in the MIC radio and showed high values of MIC in most strains. The resistance developed was not lost by subculturing the resistant strain in broth medium without antibiotic. 4) The FH strain made resistant to the antibiotics had cross resistance to other macrolides. Strains resistant to some of the antibiotics had cross resistance to lincomycin and clindamycin, and strains resistant to others did not. Some strains made resistant to macrolides with cross resistance to lincomycin and clindaymycin and strains made resistant to lincomycin or clindamycin had no cross resistance to vernamycin B alpha, while all the resistant strains without cross resistance to lincomycin and clindamycin had cross resistance to vernamycin B alpha. No strain had cross resistance to vernamycin A...

Agar↗
PubMed1978

Biological glycosidation of macrolide aglycones. II. Isolation and characterization of desosaminyl-platenolide I.

Biological glycosidation of platenolide I (I), a biosynthetic intermediate of 16-membered macrolide antibiotic platenomycin aglycones, with desosamine by Streptomycetes producing 14-membered macrolide antibiotics was attempted. Streptomyces narbonensis producing narbomycin gave a new product designated as 5-O-desosaminyl-platenolide I (III), and Streptomyces venezuelae producing narbomycin and picromycin gave III together with a second new product, 5-O-desosaminyl-14-hydroxyplatenolide I (IV). A nonantibiotic-producing blocked mutant of Streptomyces platensis subsp. malvinus, a producer of platenomycins, converted III to an antibiotically active compound identified as 3-O-propionyl-5-O-desosaminyl-9-dihydro-18-oxo-platenolide I (V).

Aminoglycosides↗
PubMed1976

The effect of fetal bovine serum on polyene macrolide antibiotic cytotoxicity and antifungal activity.

The relationships between fetal bovine serum (FBS) concentration and polyene macrolide antibiotic cytotoxicity to animal cells and to fungi were evaluated. The toxicity of amphotericin B (AB) and its derivative, amphotericin B methyl ester (AME), toward KB cells was found to be directly related to fetal bovine serum concentration. At higher FBS levels, increased concentrations of AB and AME were required to reduce 72-hr KB viable cell numbers of 50% of control values. Similarly, polyene macrolide antibiotic levels required to inhibit the growth of Saccharomyces cerevisiae to 50% of controls, and for obtaining minimum fungicidal concentrations (MFC), were greater when higher levels of FBS were used. In addition, AME was less toxic than AB toward KB cells grown in media containing 2, 5, 10, 15 or 20% FBS, whereas the antifungal activities of AB and AME were similar. AME was also capable of eliminating Candida albicans, Saccharomyces cerevisiae, Aspergillus niger or Fusarium moniliforme from KB cultures at antibiotic levels which exhibited less cell toxicity than did the concentrations of AB required for a similar response. These findings indicate that AME may be a potentially useful antifungal antibiotic for tissue culture systems.

Amphotericin B↗
PubMed1977

Studies on the biosynthesis of 16-membered macrolide antibiotics using carbon-13 nuclear magnetic resonance spectroscopy.

The origin of the skeletal carbons in the lactone ring of 16-membered macrolide antiobiotics has been studied. 13C-labeled antibiotics leucomycin and tylosin, have been obtained from the culture broth of Streptomyces kitasatoensis 66-14-3 and Streptomyces fradiae C-373, respectively in the presence of appropriate 13C-labeled precursors, and 13C NMR spectra of the antibiotics thus obtained have been measured. It was shown that the aglycone of leucomycin A3 is derived from five acetates, one propionate, one butyrate, and an unknown precursor corresponding to two carbons. The formyl carbon which is characteristic of the basic 16-membered macrolides orginates from C-4 butyrate. On the other hand, the aglycone of tylosin is formed from two acetates, five propionates and one butyrate. Butyric acid and ethylmalonic acid are metabolized to propionyl-CoA or methylmolonyl-CoA through a pathway involving methylmalonyl-CoA mutase, and subsequently incorporated into the lactone ring of tylosin.

Acetates↗
PubMed1978

Investigation of polyene macrolide antibiotic-induced permeability changes in vesicles by 31P nuclear magnetic resonance.

The permeability of egg yolk lecithin (EYL) vesicles to Pr3+ has been measured by 31P nuclear magnetic resonance (nmr) spectroscopy. Measurable Pr3+ leakage into the internal aqueous compartment of EYL vesicles at ambient (21 degrees C) temperature required the presence of small (7--10 mol%) amounts of dicetyl phosphate (DCP). The permeability of DCP-containing vesicles is decreased by incorporation of sterol (cholesterol greater than ergosterol approximately 5.6-dihydroergosterol greater than zymosterol) into the lipid bilayer. Addition of the polyene macrolide antibiotic, nystatin, to DCP-containing EYL vesicles with and without sterol resulted in increased Pr3+ permeability at the three temperatures studied (21--37.5 degrees C). Permeability changes observed upon addition of nystatin to sterol-impregnated, DCP-containing vesicles varied with sterol structure: ergosterol approximately 5,6-dihydroergosterol greater than cholesterol approximately zymosterol. These results are compared with other polyene macrolide induced permeability changes on model and natural membrane systems. Permeability changes induced by nystatin in sterol-free EYL vesicles were generally greater than for comparable sterol-containing vesicles. This is attributed to a nonspecific interaction of the antibiotic with the latter vesicles.

Cell Membrane Permeability↗
PubMed1979

Combined action of semisynthetic penicillin and macrolide antibiotic on Pseudomonas aeruginosa in vitro and in vivo.

For the purpose of studying therapy for pseudomonas infection, the synergistic effect of carbenicillin and midecamycin or 9,3''-di-O-acetyl midecamycin on Pseudomonas aeruginosa were studied in vitro and in vivo. Midecamycin and 9,3''-di-O-acetyl midecamycin were effective against spheroplasts of P. aeruginosa induced by carbenicillin treatment. As a result of investigating treatment using a combination of both carbenicillin and macrolide antibiotics on mouse infection model caused by subcutaneous injection of carrageenan solution containing viable cells of P. aeruginosa, the combined treatment was demonstrated to be significantly more effective than the control's single treatment by carbenicillin or the macrolide antibiotic alone.

Animals↗
PubMed1976

In vitro susceptibility and resistance of animal staphylococci to macrolide antibiotics and related compounds.

Strains of Staphylococcus aureus isolated from poultry, pigs and cases of bovine mastitis and strains of S. hyicus isolated from pigs were examined for their susceptibility of the macrolides and other related antibiotics. The susceptibility of these strains to erythromycin, oleandomycin, tylosin, spiramycin, lincomycin, clindamycin, virginiamycin, and its components virginiamycin S and M, was tested by the quantitative plate dilution method. With S. aureus, 3 p. 100 of the bovine, 12 p. 100 of the avian and 53 p. 100 of porcine isolated were found to be resistant. With S. hyicus strains 76 p. 100 were found to be resistant. Most resistant strains showed the generalized constitutive macrolide-resistance type. Twelve p. 100 of the porcine S. aureus strains were resistant to the virginiamycin component M.

Anti-Bacterial Agents↗