A comparison of the effects of ivermectin and moxidectin on the nematode Caenorhabditis elegans

Ardelli, Bernadette F.; Stitt, Laurel E.; Tompkins, Jeffrey B.; Prichard, Roger K.

doi:10.1016/j.vetpar.2009.06.043

Cited by 62 publications

(66 citation statements)

References 32 publications

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“…However, a recent study demonstrated a higher level of efficacy for MOX than for IVM associated with lower MOX concentrations recovered within adult H. contortus worms than IVM (43), suggesting that the activity of an ML compound against resistant nematodes is not strictly related to its ability to enter and accumulate in the target. Second, differential patterns of interaction of IVM and MOX at the GluCl receptors of nematodes (2,22) but also at the mammalian GABA receptors (67) were reported previously. Knowing that there is a large diversity of ligand-gated chloride channels in nematodes, it is possible that the two drugs may have different affinities for different channels and that some ligand-gated chloride channels may be affected to different extents and may be under different selection by IVM and MOX.…”

Section: Discussionsupporting

confidence: 53%

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Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Ménez

Alberich

Kansoh

et al. 2016

Antimicrob Agents Chemother

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cIvermectin and moxidectin are the most widely administered anthelmintic macrocyclic lactones (MLs) to treat human and animal nematode infections. Their widespread and frequent use has led to a high level of resistance to these drugs. Although they have the same mode of action, differences in terms of selection for drug resistance have been reported. Our objective was to study and compare changes occurring upon ivermectin or moxidectin selection in the model nematode Caenorhabditis elegans. C. elegans worms were submitted to stepwise exposure to increasing doses of moxidectin. The sensitivity of moxidectin-selected worms to MLs was determined in a larval development assay and compared with those of wild-type and ivermectin-selected strains. Selection with either ivermectin or moxidectin led to acquired tolerance to ivermectin, moxidectin, and eprinomectin. Importantly, moxidectin was the most potent ML in both ivermectin-and moxidectin-selected strains. Interestingly, this order of potency was also observed in a resistant Haemonchus contortus isolate. In addition, ivermectin-and moxidectin-selected strains displayed constitutive overexpression of several genes involved in xenobiotic metabolism and transport. Moreover, verapamil potentiated sensitivity to ivermectin and moxidectin, demonstrating that ABC transporters play a role in ML sensitivity in ML-selected C. elegans strains. Finally, both ivermectin-and moxidectin-selected strains displayed a dye-filling-defective phenotype. Overall, this work demonstrated that selection with ivermectin or moxidectin led to cross-resistance to several MLs in nematodes and that the induction of detoxification systems and defects in the integrity of amphidial neurons are two mechanisms that appear to affect the responsiveness of worms to both ivermectin and moxidectin.T he broad-spectrum anthelmintic macrocyclic lactones (MLs) are most commonly used in veterinary medicine to treat diseases caused by gastrointestinal nematodes and external parasites in livestock (1, 2). Ivermectin (IVM) was the first ML approved for use in animals and remains today the sole ML registered for use in humans, mainly to treat onchocerciasis through mass chemotherapy. Another ML, moxidectin (MOX), was subsequently commercialized for the veterinary market and is currently being evaluated for possible use against human onchocerciasis (3). Inevitably, the intensive use of these compounds has led to the emergence of resistance in small ruminant, cattle, and some human nematode parasites (4-7). Discovering the mechanisms by which resistance to MLs occurs remains an important challenge today.There is consistent evidence that ATP-binding-cassette (ABC) transporters such as P-glycoproteins (Pgps) play an important role in multidrug resistance (MDR) in many organisms, including several nematode species. Gene expression levels of ABC transporters or allele frequencies were modified after ML selection (8-13), and they are involved in the tolerance of Caenorhabditis elegans (9, 14-16) and parasitic nematodes s...

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Section: Discussionsupporting

confidence: 53%

“…In addition, many reports described differences in the emergence of resistance (22,23). Indeed, MOX seems to select less strongly for resistance than IVM, and resistance to IVM in various species of strongyles is much more widespread than is resistance to MOX (24)(25)(26).…”

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confidence: 99%

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Ménez

Alberich

Kansoh

et al. 2016

Antimicrob Agents Chemother

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“…It should be noted that compounds like IVM are effective against Caenorhabditis elegans at concentrations 1,000-fold lower than the concentrations used here (21). However, as we did not have access to more susceptible species, we set B. xylophilus, one of the injurious pests of greatest concern in forestry, as the target for the nematicidal activity test.…”

Section: Resultsmentioning

confidence: 99%

Gene Replacement for the Generation of Designed Novel Avermectin Derivatives with Enhanced Acaricidal and Nematicidal Activities

Huang

Chen²,

Zhang

et al. 2015

Appl Environ Microbiol

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c Avermectin (AVM) and ivermectin (IVM) are potent pesticides and acaricides which have been widely used during the past 30 years. As insect resistance to AVM and IVM is greatly increasing, alternatives are urgently needed. Here, we report two novel AVM derivatives, tenvermectin A (TVM A) and TVM B, which are considered a potential new generation of agricultural and veterinary drugs. The molecules of the TVMs were designed based on structure and pharmacological property comparisons among AVM, IVM, and milbemycin (MBM). To produce TVMs, a genetically engineered strain, MHJ1011, was constructed from Streptomyces avermitilis G8-17, an AVM industrial strain. In MHJ1011, the native aveA1 gene was seamlessly replaced with milA1 from Streptomyces hygroscopicus. The total titer of the two TVMs produced by MHJ1011 reached 3,400 mg/liter. Insecticidal tests proved that TVM had enhanced activities against Tetranychus cinnabarinus and Bursaphelenchus xylophilus, as desired. This study provides a typical example of exploration for novel active compounds through a new method of polyketide synthase (PKS) reassembly for gene replacement. The results of the insecticidal tests may be of use in elucidating the structure-activity relationship of AVMs and MBMs.A vermectins (AVMs) are a series of 16-membered macrocyclic lactone derivatives with potent anthelmintic and insecticidal properties (1, 2). Ivermectin (IVM), a hydrogenated product of AVM B1, has been one of the best-selling antiparasitics since 1981 (3). However, as insect resistance to AVM (4) and IVM (5-7) is on the rise, alternatives or new products with enhanced potency and expanded spectra of activity are urgently needed.Milbemycins (MBMs) are another group of 16-membered macrolides that share similar structures with AVMs. The insecticidal activity of milbemectin (a mixture of MBMs A3 and A4) against some parasites is higher than those of AVM and IVM, while the toxicity is significantly lower (8).The structural differences among AVM, IVM, and MBM are in C-25, C-22-23, and C-13 ( Fig. 1) (9). IVM differs from AVM in C-22-23 (the former has a saturated bond, whereas the latter has a double bond in that position), but its toxicity is lower than that of AVM (10), implying that the single bond in C-22-23 should be the better structure in terms of safety. The major structural difference between IVM and MBM is a bisoleandrosyloxy substituent attached at C-13 of IVM, whereas that position is unsubstituted in MBM. Also, there are different alkyl substituents at C-25: in IVM, the substituent can be isopropyl or secondary butyl, while in MBM, it can be methyl or ethyl. However, MBM is more potent against some parasites and is safer than IVM, suggesting that one or both of the moieties in C-25 and C-13 of MBM is (are) the better structure(s) in these ways than that (those) of IVM. Another conclusion is that the two oleandroses in C-13 are important to the antiparasitic activity of IVM, since their removal will reduce the activity significantly, about 30-fold (10). Based on the curr...

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“…Ivermectin was approximately 10 times more potent than moxidectin in a variety of fly species (19). Differences in toxicity between the macrocyclic lactones are less apparent in nematodes (27); however, studies of B. malayi and Caenorhabditis elegans show differences between phenotypic effects of the drugs, suggesting that different target sites exist (32,33). While moxidectin and ivermectin have similar mechanisms of action, the existence of different binding targets is further reflected by differences in ABC transporter-mediated efflux, for example (21).…”

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confidence: 99%

In Vitro Efficacy of Moxidectin versus Ivermectin against Sarcoptes scabiei

Mounsey

Walton

Innes

et al. 2017

Antimicrob Agents Chemother

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Moxidectin is under consideration for development as a treatment for human scabies. As some arthropods show decreased sensitivity to moxidectin relative to ivermectin, it was important to assess this for Sarcoptes scabiei. In vitro assays showed that the concentration of moxidectin required to kill 50% of mites was lower than that of ivermectin (0.5 M versus 1.8 M at 24 h; P Ͻ 0.0001). This finding provides further support for moxidectin as a candidate for the treatment of human scabies.

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A comparison of the effects of ivermectin and moxidectin on the nematode Caenorhabditis elegans

Cited by 62 publications

References 32 publications

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Gene Replacement for the Generation of Designed Novel Avermectin Derivatives with Enhanced Acaricidal and Nematicidal Activities

In Vitro Efficacy of Moxidectin versus Ivermectin against Sarcoptes scabiei

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