Review

Authors: Daniel Aowicki, Adam Huczyński

In this paper structural and microbiological studies on the ionophorous antibiotic monensin A and its derivatives have been collected. Monensin A is an ionophore which selectively complexes and transports sodium cation across lipid membranes, and therefore it shows a variety of biological properties. This antibiotic is commonly used as coccidiostat and nonhormonal growth promoter. The paper focuses on both the latest and earlier achievements concerning monensin A antimicrobial activity. The activities of monensin derivatives, including modifications of hydroxyl groups and carboxyl group, are also presented.

Topics: Amides; Anti-Infective Agents; Cations; Coccidiostats; Crystallography, X-Ray; Drug Design; Ionophores; Microbial Sensitivity Tests; Molecular Structure; Monensin; Protein Conformation; Structure-Activity Relationship

PubMed: 23509771
DOI: 10.1155/2013/742149

Authors: Kevin Chiem, Aitor Nogales, Maria Lorenzo...

Monkeypox virus (MPXV) infections in humans have historically been restricted to regions of endemicity in Africa. However, in 2022, an alarming number of MPXV cases were reported globally, with evidence of person-to-person transmission. Because of this, the World Health Organization (WHO) declared the MPXV outbreak a public health emergency of international concern. The supply of MPXV vaccines is limited, and only two antivirals, tecovirimat and brincidofovir, approved by the U.S. Food and Drug Administration (FDA) for the treatment of smallpox, are currently available for the treatment of MPXV infection. Here, we evaluated 19 compounds previously shown to inhibit different RNA viruses for their ability to inhibit orthopoxvirus infections. We first used recombinant vaccinia virus (rVACV) expressing fluorescence (mScarlet or green fluorescent protein [GFP]) and luciferase (Nluc) reporter genes to identify compounds with antiorthopoxvirus activity. Seven compounds from the ReFRAME library (antimycin A, mycophenolic acid, AVN-944, pyrazofurin, mycophenolate mofetil, azaribine, and brequinar) and six compounds from the NPC library (buparvaquone, valinomycin, narasin, monensin, rotenone, and mubritinib) showed inhibitory activity against rVACV. Notably, the anti-VACV activity of some of the compounds in the ReFRAME library (antimycin A, mycophenolic acid, AVN-944, mycophenolate mofetil, and brequinar) and all the compounds from the NPC library (buparvaquone, valinomycin, narasin, monensin, rotenone, and mubritinib) were confirmed with MPXV, demonstrating their inhibitory activity against two orthopoxviruses. Despite the eradication of smallpox, some orthopoxviruses remain important human pathogens, as exemplified by the recent 2022 monkeypox virus (MPXV) outbreak. Although smallpox vaccines are effective against MPXV, access to those vaccines is limited. In addition, current antiviral treatment against MPXV infections is limited to the use of the FDA-approved drugs tecovirimat and brincidofovir. Thus, there is an urgent need to identify novel antivirals for the treatment of MPXV infection and other potentially zoonotic orthopoxvirus infections. Here, we show that 13 compounds, derived from two different libraries, previously found to inhibit several RNA viruses, also inhibit VACV. Notably, 11 compounds also displayed inhibitory activity against MPXV.

Topics: Humans; Mpox, Monkeypox; Mycophenolic Acid; Smallpox; Antimycin A; Monensin; Rotenone; Valinomycin; Monkeypox virus; Antiviral Agents

PubMed: 37278625
DOI: 10.1128/spectrum.04745-22

Authors: Jielu Liu, Mu Nie, Caijuan Dong...

Asthma is a common respiratory disease associated with airway hyperresponsiveness (AHR), airway inflammation and mast cell (MC) accumulation in the lung. Monensin, an ionophoric antibiotic, has been shown to induce apoptosis of human MCs. The aim of this study was to define the effect of monensin on MC responses, e.g., antigen induced bronchoconstriction, and on asthmatic features in models of allergic asthma. Tracheal segments from house dust mite (HDM) extract sensitized guinea pigs were isolated and exposed to monensin, followed by histological staining to quantify MCs. Both guinea pig tracheal and human bronchi were used for pharmacological studies in tissue bath systems to investigate the monensin effect on tissue viability and antigen induced bronchoconstriction. Further, an HDM-induced guinea pig asthma model was utilized to investigate the effect of monensin on AHR and airway inflammation. Monensin decreased MC number, caused MC death, and blocked the HDM or anti-IgE induced bronchoconstriction in guinea pig and human airways. In the guinea pig asthma model, HDM-induced AHR, airway inflammation and MC hyperplasia could be inhibited by repeated administration of monensin. This study indicates that monensin is an effective tool to reduce MC number and MCs are crucial for the development of asthma-like features.

Topics: Guinea Pigs; Humans; Animals; Mast Cells; Pyroglyphidae; Monensin; Asthma; Allergens; Inflammation; Disease Models, Animal

PubMed: 36344588
DOI: 10.1038/s41598-022-23486-1

Authors: Hongtao Zhang, Lei Zhang, Ganglin Ren...

Worldwide distributed coccidiosis is caused by infection of both Eimeria species and Cystoisospora in the host intestine and causes huge economic losses to the livestock industry, especially the poultry industry. The control of such diseases relies mainly on chemoprophylaxis with anticoccidials, which has led to a very common drug resistance in this field. However, the genetic mechanisms underlying resistance to many anticoccidial drugs remain unknown. In this study, strains of E. tenella resistant to 250 mg/kg monensin were generated and characterized. Forward genetic approaches based on pooled genome sequencing, including experimental evolution and linkage group selection, were used to locate candidate targets responsible for resistance to monensin and diclazuril in E. tenella. A total of 16 nonsynonymous mutants in protein-coding genes were identified in monensin-resistant strains, and two genomic regions with strong selection signals were also detected in diclazuril-resistant strains. Our study reveals the genetic characterization of the experimental evolution and linkage group selection in Eimeria species, and also provides important information that contributes to the understanding of the molecular mechanism of drug resistance in coccidia.

Topics: Animals; Monensin; Eimeria tenella; Coccidiostats; Chickens; Poultry Diseases; Coccidiosis; Eimeria

PubMed: 37247559
DOI: 10.1016/j.ijpddr.2023.05.002

Meta-Analysis

Authors: M R Rezaei Ahvanooei, M A Norouzian, A H Piray...

The aim of this study was to conduct a comprehensive review with meta-analysis to determine the effects of the dose-response relationship between monensin supplementation and dairy cow performance and milk composition. Results from 566 full-text articles and 48 articles with 52 studies were meta-analyzed for pooled estimates. Monensin supplementation up to 23 ppm increased milk production, with the optimal dose being 12.6 ppm. Monensin supplementation at doses ranging from 16 to 96 ppm increased milk production in the prepartum phase (- 28 to 0 day relative to calving). From 60 to 150 DIM, monensin supplementation up to 21 ppm had a significant positive effect on this outcome, while supplementation in the 37 to 96 ppm range caused a decrease in this variable. At 0 to 60 and > 150 DIM, monensin supplementation had no effect on milk yield. At dosages of 22 to 96 ppm, 12 to 36 ppm, and below 58 ppm and 35 ppm, respectively, monensin supplementation resulted in significant decreases in dry matter intake (DMI), milk protein percentage, milk fat percentage, and milk fat yield. Overall, based on the results of this meta-analysis and considering all variables, the recommended optimal dose of monensin could be about 16 ppm.

Topics: Animals; Cattle; Female; Diet; Dietary Supplements; Lactation; Milk; Milk Proteins; Monensin; Dose-Response Relationship, Drug; Fats

PubMed: 36631508
DOI: 10.1038/s41598-023-27395-9

Authors: M C Anjos, L C Campos, V C A Depes...

Sodium monensin is the most frequently used ionophore as a growth promoter in ruminant diets. It has numerous benefits; however its toxic effects have also been observed in several animal species. Naturally occurring cases have not yet been reported in goats. This study describes an outbreak of accidental poisoning, characterizing its clinical, laboratory and pathological findings. Thirty-seven of 40 Anglo Nubian goat kids became intoxicated after receiving a diet that was erroneously supplemented with sodium monensin. They ingested an estimated toxic dose between 25 and 39 mg/kg BW. Clinical evolution was monitored (n = 27), followed by serum creatine kinase (CK) and aspartate aminotransferase (AST) activities measurements, and blood gas analysis. Postmortem examinations were performed between 1 and 8 days of evolution (n = 14). Clinical signs began 5 h after ingestion and included reticuloruminal hypomotility, lethargy, anorexia, tachycardia, cardiac arrhythmia, wet cough, pulmonary and tracheal crackles, and serous nasal discharge. The morbidity and lethality rates were 92.5 and 62.1%, respectively. CK and AST activities increased, reaching median values of 10,860 and 1596 U/L, respectively; the hyperchloremic metabolic acidosis was mild. The lesions were characterized by degeneration and necrosis of the cardiac and skeletal muscles, pulmonary congestion and edema, and passive liver congestion. The kids essentially developed cardiomyopathy with left and right congestive heart failures. Unlike in other ruminant species, skeletal muscle functional disability was infrequent. It can be concluded that monensin is toxic to goats and should be used with caution in their diet.

Topics: Animals; Monensin; Goats; Heart; Muscle, Skeletal; Sodium

PubMed: 37857004
DOI: 10.1016/j.toxicon.2023.107314

Authors: D Ye, S K R Karnati, B Wagner...

The interaction of monensin and essential oil was hypothesized to suppress protozoa and methane production while maintaining normal rumen function. The objective of this study was to determine the effects of feeding monensin (MON) and CinnaGar (CIN, a commercial blend of cinnamaldehyde and garlic oil; Provimi North America, Brookville, OH) on ruminal fermentation characteristics. Continuous culture fermentors (n = 4) were maintained in 4 experimental periods in a 4 × 4 Latin square design. Four dietary treatments were arranged in a 2 × 2 factorial: (1) control diet, 37 g/d of dry matter (40 g/d at ∼92.5% dry matter) of a 50:50 forage:concentrate diet containing no additive; (2) MON at 11 g/909 kg of dry matter; (3) CIN at 0.0043% of dry matter; and (4) a combination of MON and CIN at the levels in (2) and (3). Treatment had no effects on protozoal populations, concentration of NHN, total N flow of effluent, production of total volatile fatty acids, or flows of conjugated linoleic acid and total C18 fatty acids. The MON decreased acetate:propionate ratio and biohydrogenation of both total C18 and 18:1 cis-9 but increased protozoal generation time, concentration of peptide, and flow of 18:1 trans-11. The MON tended to decrease protozoal counts in effluent and flow of 18:0 but tended to increase propionate production. The CIN decreased true organic matter digestibility and protozoal N flow of effluent but increased nonammonia, nonmicrobial N flow. The CIN tended to decrease protozoal counts, microbial N flow, and neutral detergent fiber digestibility but tended to increase biohydrogenation of total C18, 18:2, and 18:3. The CIN tended to increase isovalerate production. The MON and CIN tended to interact for increased methane production and bacterial N flow. A second experiment was conducted to determine the effects of MON and CIN on protozoal nitrogen and cell volume in vitro. Four treatments included (1) control (feed only), (2) feed + 0.0043% dry matter CIN, (3) feed + 2.82 μM MON, and (4) feed + CIN + MON at the same levels as in (2) and (3). With no interactions, MON addition decreased percentage of protozoa that were motile and tended to decrease cell volume at 6 h. The CIN did not affect cell count or other indicators of motility or volume at either 3 or 6 h. Under the conditions of our study, we did not detect an additive response for MON and CIN to decrease protozoal counts or methane production. A 3-dimensional method is suggested to better estimate protozoal cell volume.

Topics: Animal Feed; Animals; Diet; Digestion; Fermentation; Monensin; North America; Oils, Volatile; Protozoan Infections, Animal; Rumen

PubMed: 29605331
DOI: 10.3168/jds.2017-13646

Authors: Nikolay Petkov, Ivayla Pantcheva, Anela Ivanova...

The largely uncharted complexation chemistry of the veterinary polyether ionophores, monensic and salinomycinic acids (HL) with metal ions of type M and the known antiproliferative potential of antibiotics has provoked our interest in exploring the coordination processes between MonH/SalH and ions of Ce. (1) Methods: Novel monensinate and salinomycinate cerium(IV)-based complexes were synthesized and structurally characterized by elemental analysis, a plethora of physicochemical methods, density functional theory, molecular dynamics, and biological assays. (2) Results: The formation of coordination species of a general composition [CeL(OH)] and [CeL(NO)(OH)], depending on reaction conditions, was proven both experimentally and theoretically. The metal(IV) complexes [CeL(NO)(OH)] possess promising cytotoxic activity against the human tumor uterine cervix (HeLa) cell line, being highly selective (non-tumor embryo Lep-3 vs. HeLa) compared to cisplatin, oxaliplatin, and epirubicin.

Topics: Humans; Monensin; Cerium; Ionophores; Ions

PubMed: 37375231
DOI: 10.3390/molecules28124676

Restricted maternal nutrition and supplementation of propylene glycol, monensin sodium and rumen-protected choline chloride during late pregnancy does not affect muscle fibre characteristics of offspring.

Authors: Leila Ahmadzadeh-Gavahan, Ali Hosseinkhani, Gholamreza Hamidian...

BACKGROUND

Grazing in arid and semi-arid regions faces pregnant ewes with feed restrictions and hence affects the offspring muscle fibre characteristics. Using feed additives that enhance nutrient availability during foetal muscle development is expected to alter offspring skeletal muscle characteristics.

OBJECTIVES

This study evaluated the effect of maternal restricted nutrition and supplementation of propylene glycol, monensin sodium and rumen-protected choline chloride on lamb's muscle fibre characteristics.

METHODS

Forty-eight Ghezel ewes were randomly allocated to one of six diets (N = 8) during the last 6 weeks of gestation: ad libitum feed intake (AL); restricted feeding (RF); restricted feeding containing propylene glycol (PG); restricted feeding containing propylene glycol and monensin sodium (MS); restricted feeding containing propylene glycol and rumen-protected choline chloride (RPC); restricted feeding containing propylene glycol, monensin sodium and rumen-protected choline chloride (PMC). The muscle samples were obtained from the semitendinosus muscle of 2-week-old male lambs (n = 5/treatment) via biopsy and were stained and classified as fibre types I, IIA and IIB.

RESULTS

Pre-parturient maternal feed restriction and administration of propylene glycol, monensin sodium and rumen-protected choline chloride had no significant effect on fibre-type composition, fibre density of muscle, muscle cross-sectional area and volume density of fibres (p > 0.05).

CONCLUSIONS

Either maternal dietary restriction or supplementation of nutrient flux-involved additives during late pregnancy did not alter muscle fibre development and had no short-term effects on muscle properties of the resulting offspring as myogenesis occurs in early and mid-gestation, not late gestation. Therefore, maternal nutrition may not be a problematic issue in sheep production in arid and semi-arid areas.

Topics: Pregnancy; Animals; Sheep; Female; Male; Monensin; Choline; Rumen; Propylene Glycol; Muscle Fibers, Skeletal; Dietary Supplements

PubMed: 37556348
DOI: 10.1002/vms3.1239

Authors: Alicja Urbaniak, Megan R Reed, Billie Heflin...

Glioblastoma (GBM) remains the most frequently diagnosed primary malignant brain cancer in adults. Despite recent progress in understanding the biology of GBM, the clinical outcome for patients remains poor, with a median survival of approximately one year after diagnosis. One factor contributing to failure in clinical trials is the fact that traditional models used in GBM drug discovery poorly recapitulate patient tumors. Previous studies have shown that monensin (MON) analogs, namely esters and amides on C-26 were potent towards various types of cancer cell lines. In the present study we have investigated the activity of these molecules in GBM organoids, as well as in a host:tumor organoid model. Using a mini-ring cell viability assay we have identified seven analogs (IC = 91.5 ± 54.4-291.7 ± 68.8 nM) more potent than parent MON (IC = 612.6 ± 184.4 nM). Five of these compounds induced substantial DNA fragmentation in GBM organoids, suggestive of apoptotic cell death. The most active analog, compound 1, significantly reduced GBM cell migration, induced PARP degradation, diminished phosphorylation of STAT3, Akt and GSK3β, increased ɣH2AX signaling and upregulated expression of the autophagy associated marker LC3-II. To investigate the activity of MON and compound 1 in a tumor microenvironment, we developed human cerebral organoids (COs) from human induced pluripotent stem cells (iPSCs). The COs showed features of early developing brain such as multiple neural rosettes with a proliferative zone of neural stem cells (Nestin+), neurons (TUJ1 +), primitive ventricular system (SOX2 +/Ki67 +), intermediate zone (TBR2 +) and cortical plate (MAP2 +). In order to generate host:tumor organoids, we co-cultured RFP-labeled U87MG cells with fully formed COs. Compound 1 and MON reduced U87MG tumor size in the COs after four days of treatment and induced a significant reduction of PARP expression. These findings highlight the therapeutic potential of MON analogs towards GBM and support the application of organoid models in anti-cancer drug discovery.

Topics: Adult; Brain Neoplasms; Cell Line, Tumor; Glioblastoma; Humans; Induced Pluripotent Stem Cells; Monensin; Organoids; Poly(ADP-ribose) Polymerase Inhibitors; Tumor Microenvironment

PubMed: 36076555
DOI: 10.1016/j.biopha.2022.113440