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PubMed1989

New macrolides active against Streptococcus pyogenes with inducible or constitutive type of macrolide-lincosamide-streptogramin B resistance.

Macrolide-resistant bacteria can be classified as inducibly resistant or constitutively resistant. Inducibly resistant bacteria are resistant to 14-membered macrolides, such as erythromycin and clarithromycin (A-56268), but are susceptible to the 16-membered macrolides, such as tylosin and spiramycin, as well as to clindamycin. Constitutively resistant bacteria are resistant to macrolide-lincosamide-streptogramin B antibiotics. In this study, the MICs of several erythromycin and clarithromycin analogs against macrolide-susceptible and macrolide-resistant Streptococcus pyogenes strains were determined. Four 11,12-carbamate analogs of clarithromycin had lower MICs than erythromycin did against S. pyogenes with the inducible or constitutive type of macrolide-lincosamide-streptogramin B resistance. Five 11,12-carbonate analogs of erythromycin with modifications at the 4" position of cladinose had lower MICs than did erythromycin against S. pyogenes with the constitutive type of resistance, and one of these compounds, which had a naphthyl-glycyl substitution at the 4" position, had a lower MIC than erythromycin against both the inducibly resistant and constitutively resistant strains. Two analogs of erythromycin with a modification on the 4" position of cladinose had lower MICs than erythromycin did against the constitutively resistant organisms but not against the inducibly resistant organisms. Thus, 14-membered macrolides can be modified so as to confer a low MIC when tested in vitro.

Aminoglycosides↗

PubMed1992

Inducible resistance to a 16-membered macrolide, mycinamicin, in Staphylococcus aureus resistant to 14-membered macrolides and streptogramin B antibiotics.

Staphylococcus aureus 8325(pEP2104), a transductant derived from S. aureus PM2104 isolated clinically in Hungary (L. Janosi, and E. Ban, Acta Microbiol. Acad. Sci. Hung., 29: 187-200, 1982), exhibited an inducible resistance to the 14-membered macrolides [erythromycin (EM) and oleandomycin (OL)] and streptogramin B (MKM-B) antibiotics, but not to the 16-membered macrolides and lincosamides. This resistance was referred to as PMS-resistance phenotype (L. Jánosi, Y. Nakajima, and H. Hashimoto, Microbiol. Immunol., 34: 723-735, 1990). In addition to EM, OL, and MKM-B, however, the strain was recently and first observed to have inducible resistance to mycinamicin, a 16-membered ring macrolide. Thereby, we propose that the reference stated just above as PMS-resistance has to be extended to such 16-membered macrolides as mycinamicin. An optimum concentration of erythromycin or oleandomycin for induction of PMS-resistance was 1.35 mu g/ml in the strain 8325(pEP2104). The concentration was about 30 times as great as that (0.05 mu g/ml) required for induction of well-known co-resistance to macrolide-lincosamide-streptogramin B antibiotics in S. aureus ISP447.

Anti-Bacterial Agents↗

PubMed1992

Purification and characterization of macrolide 2'-phosphotransferase type II from a strain of Escherichia coli highly resistant to macrolide antibiotics.

The resistance mechanism of Escherichia coli BM2506 to macrolides was found to be due to inactivation. Inactivated oleandomycin was identified as oleandomycin 2'-phosphate by thin-layer chromatography. A new type of macrolide-phosphorylating enzyme, macrolide 2'-phosphotransferase type II (MPH(2')II), was detected, purified 95-fold and its enzymological properties investigated. MPH(2')II was a constitutive intracellular enzyme which showed high levels of activity with both 14-member-ring and 16-member-ring macrolides. The optimum pH for the inactivation of oleandomycin was 8.2 and the optimum temperature of the reaction was 40 degrees C. Enzyme activity was lost by heat treatment at 60 degrees C for 1 min. The isoelectric point and M(r) of the enzyme were 5.3 and 48,000, respectively. Purine nucleotides, such as ITP, GTP and ATP, were effective as cofactors in the inactivation of macrolides. An inhibitory effect of iodine, EDTA, or divalent cations on MPH(2')II activity was observed.

Anti-Bacterial Agents↗

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↗

PubMed1975

Sequence of biosynthesis of the components of the polyene macrolides candidin and candihexin: macrolide aglycones as intracellular components.

A sequential formation of the single components of the polyene macrolide candidin complex (heptaene) has been found. In addition to the three components occurring in the candidin complex at the end of the fermentation, two other "early" all-trans heptaene components have been characterized. They exist only during the phase of active biosynthesis of candidin. Two of the components of the polyene macrolide candihexin complex (hexaene) that have been described as lacking amino sugar were the only intracellular (mycelium-associated) components observed under conditions in which no extracellular polyene remained attached to the producing cell. The results indicate that glycosylation of the macrolide ring takes place during the secretion process.

Antifungal Agents↗

PubMed1989

[Comparison of the in vitro post-antibiotic effect of C14 macrolides (erythromycin and roxithromycin) and C16 macrolides (josamycin and spiramycin) against Staphylococcus aureus].

In vitro post-antibiotic effect (PAE) induced by erythromycin, roxithromycin, josamycin and spiramycin has been compared on Staphylococcus aureus. Three MLSB sensitive and three MLSB inducible resistant S. aureus strains have been used. delta t was the time required for culture to increase by 1 log10 after drug removal in comparison with controls. For erythromycin and roxithromycin delta t ranged from 6 minutes at 1 x MIC to 48 minutes at 4 x MIC (average of the six strains at 4 x MIC: 33 minutes). For josamycin and spiramycin, delta t ranged from 36 at 1/2 x MIC to 138 minutes at 4 x MIC (average at 4 x MIC: 101 minutes). No difference was observed between MLSB sensitive and MLSB inducible resistant S. aureus strains. In our experimental conditions, PAEs observed with josamycin and spiramycin (16-membered-ring macrolides) were 2.5 to 3 times longer than those observed with erythromycin and roxithromycin (14-membered-ring macrolides). These results added to biological differences previously observed between 14-membered-ring and 16-membered-ring macrolides.

Erythromycin↗

PubMed1977

Macrolide resistance in Staphylococcus aureus: inducers of macrolide resistance.

Several macrolide-, lincosamide-, and streptogramin B-type (MLS) antibiotics were tested as inducers of erythromycin A (EM)-resistant [(14)C]leucine incorporation. Only 14-membered-ring macrolides having a glycosidically linked 6-deoxy sugar at the C-3 position of the lactone ring and the structurally dissimilar lincosamide, celesticetin, showed inducer activity. Modifications of EM at the C-4'' position of cladinose can apparently destroy the inducer property but do not affect the inhibitory properties of the antibiotic. The findings clearly show that inducer and inhibitor activities can be dissociated and are consistent with the concept that distinct binding/receptor sites are utilized for inhibition of ribosome function and induction of resistance.

Anti-Bacterial Agents↗

PubMed1989

Binding of novel macrolide structures to macrolides-lincosamides-streptogramin B-resistant ribosomes inhibits protein synthesis and bacterial growth.

Dimethylation of adenine 2058 in 23S rRNA renders bacteria resistant to macrolides, lincosamides, and streptogramin B (MLS resistance), because the antibiotic binding site on the altered 50S ribosomal subunit is no longer accessible. We now report that certain 6-O-methyl-11,12-cyclic carbamate derivatives of erythromycin are able to bind to dimethylated MLS-resistant 50S ribosomal subunits, thus inhibiting protein synthesis and cell growth. One of these novel structures, an 11-deoxy-11-(carboxyamino)-6-O-methylerythromycin A 11,12-(cyclic ester) derivative, structure 1a, was studied in detail. It inhibited in vitro protein synthesis in extracts prepared from both susceptible and MLS-resistant Bacillus subtilis with 50% inhibitory concentrations of 0.4 and 20 microM, respectively. The derivative bound specifically to a single site on the 50S subunit of MLS-resistant ribosomes prepared from B. subtilis and Staphylococcus aureus, and no binding to 30S subunits was observed. The association rate constant of derivative 1a with sensitive and resistant ribosomes was 100- and 500-fold slower, respectively, than that of the parent compound, erythromycin, with sensitive ribosomes. The dissociation rate constant of 1a from sensitive and resistant ribosomes was 50- to 100-fold slower than the rate of erythromycin dissociation from sensitive ribosomes. Furthermore, 1a binding to sensitive 50S subunits led to induction of ermC and ermD, while binding to resistant 50S subunits did not, showing that perturbation of sensitive and resistant 50S subunit function by 1a differs. These data demonstrated that 1a is unique in its interaction with MLS-resistant ribosomes and that this interaction causes a novel allosteric perturbation of ribosome function.

Anti-Bacterial Agents↗

PubMed1977

Macrolide resistance in Staphylococcus aureus: induction of macrolide-resistant protein synthesis.

Induction of resistance to macrolide-, lincosamide-, and streptogramin B-type antibiotics in Staphylococcus aureus was studied by monitoring the appearance of erythromycin A (EM)-resistant [(14)C]leucine incorporation. Examination of the induction process revealed saturation kinetics and a time course much like that reported for penicillinase in gram-positive bacteria. Induction kinetics in exponentially growing cells were sigmoidal and appeared to reach a maximum and constant rate when growth reached stationary phase. Since the induction of EM-resistant colony-forming ability was complete within 60 min, ribosome modification cannot be limited to a fraction of the population and must occur in essentially every cell. However, EM-resistant growth was expressed in cells where less than half the [(14)C]leucine-incorporating activity was resistant to EM. This suggests that resistance requires that only a threshold level of ribosome modification be exceeded and that, once exceeded, resistance is dominant to sensitivity.

Anti-Bacterial Agents↗

PubMed1990

Role of an energy-dependent efflux pump in plasmid pNE24-mediated resistance to 14- and 15-membered macrolides in Staphylococcus epidermidis.

We have elucidated a new mechanism for bacterial resistance to the 14-membered macrolides oleandomycin and erythromycin and the 15-membered macrolide azithromycin. Plasmid pNE24, previously isolated from a clinical specimen of Staphylococcus epidermidis, was characterized as causing resistance to 14-membered but not 16-membered macrolides by a mechanism suggested to involve reduced antibiotic permeation of bacterial cells (B. C. Lampson, W. von David, and J. T. Parisi, Antimicrob. Agents Chemother. 30:653-658, 1986). Our recent investigations have demonstrated that S. epidermidis 958-2 containing plasmid pNE24 also contains an energy-dependent macrolide efflux pump which maintains intracellular antibiotic concentrations below those required for binding to ribosomes. Thus, when strain 958-2 was pretreated with the inhibitor carbonyl cyanide m-chlorophenylhydrazone (CCCP), macrolide accumulated at the same rate and to the same extent as in CCCP-treated or untreated control cells lacking plasmid pNE24 (strain 958-1). In contrast, macrolide did not accumulate in energy-competent strain 958-2 but did accumulate to levels equal to those of ribosomes immediately following CCCP addition. Furthermore, intracellular macrolide was excreted and bacteria resumed growth when CCCP but not macrolide was removed from the growth medium. As expected, the 16-membered macrolide niddamycin accumulated to the same level in energy-competent strains 958-1 and 958-2 at the same rapid rate. Macrolide incubated with lysates prepared from both strains or recovered from cells of strain 958-2 was unmodified and bound to ribosomes from strains 958-1 and 958-2 with identical affinities and kinetics, thus precluding a role for ribosome or drug alteration in the resistance mechanism. We conclude that the presence of plasmid pNE24 results in specific energy-dependent efflux of 14- and 15-membered macrolides.

Aminoglycosides↗

PubMed1992

Pharmacokinetic drug interactions of macrolides.

The macrolide antibiotics include natural members, prodrugs and semisynthetic derivatives. These drugs are indicated in a variety of infections and are often combined with other drug therapies, thus creating the potential for pharmacokinetic interactions. Macrolides can both inhibit drug metabolism in the liver by complex formation and inactivation of microsomal drug oxidising enzymes and also interfere with microorganisms of the enteric flora through their antibiotic effects. Over the past 20 years, a number of reports have incriminated macrolides as a potential source of clinically severe drug interactions. However, differences have been found between the various macrolides in this regard and not all macrolides are responsible for drug interactions. With the recent advent of many semisynthetic macrolide antibiotics it is now evident that they may be classified into 3 different groups in causing drug interactions. The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes and the consequent formation of inactive cytochrome P450-metabolite complexes. The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin and midecamycin) form complexes to a lesser extent and rarely produce drug interactions. The last group (e.g. spiramycin, rokitamycin, dirithromycin and azithromycin) do not inactivate cytochrome P450 and are unable to modify the pharmacokinetics of other compounds. It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 and the formation in vivo or in vitro of an inhibitory cytochrome P450-iron-nitrosoalkane metabolite complex: the presence in the macrolide molecules of a non-hindered readily accessible N-dimethylamino group and the hydrophobic character of the drug. Troleandomycin ranks first as a potent inhibitor of microsomal liver enzymes, causing a significant decrease of the metabolism of methylprednisolone, theophylline, carbamazepine, phenazone (antipyrine) and triazolam. Troleandomycin can cause ergotism in patients receiving ergot alkaloids and cholestatic jaundice in those taking oral contraceptives. Erythromycin and its different prodrugs appear to be less potent inhibitors of drug metabolism. Case reports and controlled studies have, however, shown that erythromycins may interact with theophylline, carbamazepine, methylprednisolone, warfarin, cyclosporin, triazolam, midazolam, alfentanil, disopyramide and bromocriptine, decreasing drug clearance. The bioavailability of digoxin appears also to be increased by erythromycin in patients excreting high amounts of reduced digoxin metabolites, probably due to destruction of enteric flora responsible for the formation of these compounds. These incriminated macrolide antibiotics should not be administered concomitantly with other drugs known to be affected metabolically by them, or at the very least, combined administration should be carried out only with careful patient monitoring.(ABSTRACT TRUNCATED AT 400 WORDS)

Anti-Bacterial Agents↗

PubMed1991

The in vitro activity of some 14-, 15- and 16- membered macrolides against Staphylococcus spp., Legionella spp., Mycoplasma spp. and Ureaplasma urealyticum.

Erythromycin is a macrolide antimicrobial chemically comprised of a 14-membered lactone ring substituted with a neutral (cladinose) and an amino (desosamine) sugar. Recently, a number of new macrolide molecules have been identified containing either 14-, 15- or 16-membered substituted lactone rings. In this study the authors have determined the in vitro activity of roxithromycin and clarithromycin (both 14-membered macrolides), azithromycin (a 15-membered macrolide or azalide) and midecamycin acetate (a 16-membered macrolide) against clinical isolates of Staphylococcus spp., (including methicillin-susceptible and -resistant isolates), Legionella spp., Mycoplasma spp. and Ureaplasma urealyticum. Minimum inhibitory concentrations of the macrolides for the clinical isolates of Staphylococcus spp. examined were widely distributed. However, midecamycin acetate retained activity against those isolates of Staphylococcus spp. exhibiting inducible resistance to erythromycin and the other macrolides tested. Isolates characterised by constitutive resistance to erythromycin were also resistant to midecamycin acetate. All of the macrolides were very active against Legionella spp., with clarithromycin demonstrating the greatest potency (MIC range: less than or equal to 0.03-0.06 mg/l). Isolates of Mycoplasma pneumoniae and Ureaplasma urealyticum were susceptible to all of the macrolides tested. However, erythromycin, roxithromycin, clarithromycin and azithromycin were poorly active against isolates of Mycoplasma hominis. By contrast, the same isolates were susceptible (MIC range: 0.008-0.12 mg/l) to midecamycin acetate.

Anti-Bacterial Agents↗

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↗

PubMed1991

Comparative activity of macrolides against Toxoplasma gondii demonstrating utility of an in vitro microassay.

The utility of spiramycin for preventing transplacental transmission of toxoplasmosis and the efficacy of conventional macrolides against Toxoplasma gondii are subjects of active debate. An in vitro microassay was developed to determine the relative inhibitory activity against T. gondii of 24 conventional macrolides derived from erythromycin and tylosin (14- and 16-membered macrolides, respectively). Macrolides and T. gondii RH tachyzoites were added to monolayers of BT cells grown in 96-well plates. Plates were incubated for 20 h at 37 degrees C, and the growth of T. gondii was then measured by the selective incorporation of [3H]uracil in trichloroacetic acid-precipitable material during an additional incubation of 20 h. Dose-response curves and 50 and 90% inhibitory concentrations (IC50 and IC90, respectively) were determined for each drug. Microscopic examination was performed on stained replicates of the infected monolayers, and the relative toxicities of the drugs for host cells were determined. Spiramycin and tylosin showed only limited activity against T. gondii (IC50 of 20.16 and 20.00 micrograms/ml, respectively). Erythromycin and azithromycin had a better anti-Toxoplasma activity with IC50 of 14.38 and 8.61 micrograms/ml, respectively, whereas drugs like desmycosin, dirithromycin, and roxithromycin had no detectable activity. Although many macrolides inhibited intracellular proliferation of T. gondii, azithromycin was the only macrolide demonstrating prolonged inhibitory activity on the replication of intracellular tachyzoites. We conclude that conventional 14- and 16-membered macrolides often interfere with the growth of, but may not kill, T. gondii RH tachyzoites in vitro.

Animals↗

PubMed1990

Role of protonated and neutral forms of macrolides in binding to ribosomes from gram-positive and gram-negative bacteria.

Erythromycin binds to a single site on the bacterial 50S ribosomal subunit and perturbs protein synthesis. However, erythromycin contains desosamine and thus exists in both protonated (greater than 96%) and neutral (less than 4%) forms at physiological pH because of the pKa of the dimethylamino group. We therefore examined the relative roles of both forms in binding to ribosomes isolated from two species each of gram-positive and gram-negative bacteria. We developed a system to directly measure the forward (association) rate constant of formation of the macrolide-ribosome complex, and we have measured both the forward and reverse (dissociation) rate constants as a function of pH. Forward rate constants and binding affinity did not correlate with pH when the interaction of erythromycin with ribosomes from both gram-positive and gram-negative bacteria was examined, demonstrating that the protonated form of this macrolide binds to ribosomes. Conversely, the neutral form of macrolide cannot be the sole binding species and appears to bind with the same kinetics as the protonated form. Forward rate constants were 3- to 4-fold greater at physiological pH, and binding affinity calculated from rate constants was 5- to 10-fold greater than previously estimated. Similar results were obtained with azithromycin, a novel 15-membered macrolide that contains an additional tertiary amine in the macrolide ring. Ribosome- and macrolide-specific kinetic parameters were demonstrated at neutral pH and may be related to the potency of the two macrolides against gram-positive and gram-negative bacteria.

Azithromycin↗

PubMed1989

Clinical pharmacokinetic properties of the macrolide antibiotics. Effects of age and various pathophysiological states (Part I).

The pharmacokinetic aspects in humans of macrolide antibiotics that are currently or soon to be on the market (i.e. erythromycin, oleandomycin, spiramycin, josamycin, midecamycin, miocamycin, rosaramycin, roxithromycin and azithromycin) are reviewed. Macrolide antibiotics are basic compounds, poorly soluble in water, which are mostly absorbed in the alkaline intestinal environment. They are acid unstable, but the newer semisynthetic derivatives (i.e. roxithromycin and azithromycin) are characterised by increased stability under acidic conditions. Macrolides are highly liposoluble and consequently penetrate well into tissue, especially bronchial secretions, prostatic tissue, middle ear exudates and bone tissues, as evidenced by tissue/serum concentration ratios greater than 1. They do not penetrate well into the CSF. Macrolides undergo extensive biotransformation in the liver. With a few exceptions (e.g. miocamycin), the metabolites of these drugs are characterised by little or no antimicrobial activity. Plasma protein binding is variable from one compound to another. At therapeutic concentrations, protein-bound erythromycin accounts for 80 to 90% of the total drug present in the blood, and the fraction is 95% for roxithromycin. The lowest values of protein-bound fraction are observed for midecamycin and josamycin (about 15%), and intermediate values are reported for spiramycin and miocamycin. However, the clinical relevance of this parameter is not clearly established. Plasma half-life (t1/2) values vary for the macrolides described: erythromycin, oleandomycin, josamycin and miocamycin have a t1/2 ranging from 1 to 2 hours; spiramycin, erythromycin stearate, the mercaptosuccinate salt of propionyl erythromycin and rosaramicin have an intermediate t1/2 (about 7, 6.5, 5 and 4.5 hours, respectively); the newer semisynthetic compounds roxithromycin and azithromycin are characterised by high t1/2 values (i.e. 11 and 41 hours, respectively). Under normal conditions, the major route of elimination is the liver. Renal elimination also takes place but it contributes to total clearance only to a small degree, as evidenced by low renal clearance values. The degree of modification of macrolide pharmacokinetics by renal insufficiency or hepatic disease is usually not considered clinically relevant, and no recommendation for dose modification is necessary in these patients. The pharmacokinetics of macrolides are modified in elderly patients. Accordingly, their use must be accompanied by a closer than usual clinical monitoring of the older patient.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗

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↗