Boron-Pleuromutilins as Anti-<i>Wolbachia</i> Agents with Potential for Treatment of Onchocerciasis and Lymphatic Filariasis

Jacobs, Robert T.; Lunde, Christopher S.; Freund, Yvonne R.; Hernandez, Vincent; Li, Xianfeng; Xia, Yi; Carter, David S.; Berry, Pamela; Halladay, Jason; Rock, Fernando; Stefanakis, Rianna; Easom, Eric E.; Plattner, Jacob J.; Ford, Louise; Johnston, Kelly L.; Cook, Darren; Clare, Rachel H.; Cassidy, Andrew; Myhill, Laura J.; Tyrer, Hayley E.; Gamble, Joanne; Guimarães, Ana Flávia Bereta Coelho; Steven, Andrew; Lenz, Franziska; Ehrens, Alexandra; Frohberger, Stefan J.; Koschel, Marianne; Hoerauf, Achim; Hübner, Marc P.; McNamara, Case W.; Bakowski, Malina A.; Turner, Joseph D.; Taylor, Mark J.; Ward, Stephen A.

doi:10.1021/acs.jmedchem.8b01854

Cited by 38 publications

(46 citation statements)

References 53 publications

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“…Body weights of mice were determined daily during the treatment and the drugs were given in a volume of 10 ml/kg body weight. In a previous study, a 14-day twice-daily treatment of 50 mg/kg AN11251 was shown to deplete > 99% of Wolbachia in the L. sigmodontis mouse model [23]. In the current study, shorter treatment regimens of 7 and 10 days were tested in order to achieve the target candidate profile.…”

Section: Study Design and L Sigmodontis Infectionmentioning

confidence: 93%

“…AN11251 was provided by Anacor Pharmaceuticals (Palo Alto, CA) and was > 98% pure [23]. The compound was formulated in 1% carboxymethyl cellulose (CMC) + 0.1% Tween80 or in 10% dimethyl sulfoxide (DMSO) (Sigma Aldrich, St. Louis, MO, USA) in phosphate-buffered saline (PBS)/1% CMC/0.1% Tween80 (see S1 Table).…”

Section: Test Compoundsmentioning

confidence: 99%

“…X: untreated, black triangle upside down: 7-day treatment, black triangle upside: 10-day treatment, black square: 14-day treatment. #: already published data [23]. Statistical significance was analyzed by Kruskal-Wallis followed by Dunn's multiple comparison post-hoc test.…”

Section: Wolbachia Reduction By An11251 At 200 Mg/kg Bid Is Superior mentioning

confidence: 99%

“…Like doxycycline, pleuromutilins are ribosomal protein synthesis inhibitors, targeting predominantly Gram-positive bacteria [22]. The boron-pleuromutilin derivative AN11251 represents an anti-Wolbachia pre-clinical candidate that showed excellent pharmacokinetic properties and reduced Wolbachia loads in B. malayi and L. sigmodontis in rodents after oral administration [23]. Twice-daily treatment with 25 mg/kg AN11251 for 14 days achieved a Wolbachia reduction of 98.8% in B. malayi larvae and 16.6% Wolbachia reduction in B. malayi adults in SCID mice; Administration of 50 mg/kg AN11251 twice a day for 2 weeks resulted in a Wolbachia reduction of 99.7% in BALB/ c mice infected with L. sigmodontis [23].…”

Section: Introductionmentioning

confidence: 99%

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In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis

Ehrens¹,

Lunde²,

Jacobs³

et al. 2020

PLoS Negl Trop Dis

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The elimination of filarial diseases such as onchocerciasis and lymphatic filariasis is hampered by the lack of a macrofilaricidal-adult worm killing-drug. In the present study, we tested the in vivo efficacy of AN11251, a boron-pleuromutilin that targets endosymbiotic Wolbachia bacteria from filarial nematodes and compared its efficacy to doxycycline and rifampicin. Doxycycline and rifampicin were previously shown to deplete Wolbachia endosymbionts leading to a permanent sterilization of the female adult filariae and adult worm death in human clinical studies. Twice-daily oral treatment of Litomosoides sigmodontisinfected mice with 200 mg/kg AN11251 for 10 days achieved a Wolbachia depletion > 99.9% in the adult worms, exceeding the Wolbachia reduction by 10-day treatments with bioequivalent human doses of doxycycline and a similar reduction as high-dose rifampicin (35 mg/kg). Wolbachia reductions of > 99% were also accomplished by 14 days of oral AN11251 at a lower twice-daily dose (50 mg/kg) or once-per-day 200 mg/kg AN11251 treatments. The combinations tested of AN11251 with doxycycline had no clear beneficial impact on Wolbachia depletion, achieving a > 97% Wolbachia reduction with 7 days of treatment.These results indicate that AN11251 is superior to doxycycline and comparable to highdose rifampicin in the L. sigmodontis mouse model, allowing treatment regimens as short as 10-14 days. Therefore, AN11251 represents a promising pre-clinical candidate that was identified in the L. sigmodontis model, and could be further evaluated and developed as potential clinical candidate for human lymphatic filariasis and onchocerciasis.PLOS Neglected Tropical Diseases | https://doi.Onchocerciasis and lymphatic filariasis are human filarial tropical diseases, which can cause blindness and severe dermatitis (onchocerciasis) or lymphedema and hydrocele (lymphatic filariasis). Current strategies to eliminate these diseases include the mass drug administration (MDA) of drugs that target the progeny of the filariae, the microfilariae, and temporarily inhibit filarial embryogenesis and, therefore, the transmission of the disease. However, MDA has several limitations that delay the goal of elimination including the lack of a drug with a short term regimen and a potent macrofilaricidal effect. As an alternative approach, the antibiotic doxycycline has been proven to be effective in depleting Wolbachia endosymbionts from adult filariae, which then leads to permanent sterilization and death of the adult worms. Due to contraindications for doxycycline and prolonged treatment regimen of at least 4 weeks, there is an urgent need for new anti-filarial drugs with an improved safety profile and shorter regimens. The current study demonstrates that the boron-pleuromutilin derivative AN11251 provides an excellent in vivo anti-Wolbachia depletion in the Litomosoides sigmodontis filarial mouse model that is superior to doxycycline and comparable to rifampicin, allowing for regimens as short as 10-14 days. Combination with doxycycline for 7 da...

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Section: Study Design and L Sigmodontis Infectionmentioning

confidence: 93%

Section: Test Compoundsmentioning

confidence: 99%

Section: Wolbachia Reduction By An11251 At 200 Mg/kg Bid Is Superior mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis

Ehrens¹,

Lunde²,

Jacobs³

et al. 2020

PLoS Negl Trop Dis

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“…Pleuromutilins (PLEs) are a family of broad‐spectrum antimicrobials capable of effectively inhibiting a range of Gram positive and negative bacteria (Goethe, Heuer, Ma, Wang, & Herzon, 2019; Jacobs et al., 2019). In modern animal husbandry, PLEs are extensively employed in preventing and treating swine enzootic pneumonia, swine dysentery, and mycoplasma infection in poultry and livestock (Duijkeren et al., 2009; Šperling, Čížek, & Smola, 2014; Stipkovits et al., 2005; Wattanaphansak, Singer, & Gebhart, 2009).…”

Section: Introductionmentioning

confidence: 99%

A highly sensitive monoclonal antibody−based paper sensor for simultaneously detecting valnemulin and tiamulin in porcine liver

Sun

et al. 2020

Journal of Food Science

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Valnemulin (VAL) and tiamulin (TIA) are pleuromutilin antibiotics used primarily for treating bacterial infections in swine or other food animals. Furthermore, VAL and TIA are also employed as feed additives to promote animal growth. However, the illegal use of VAL and TIA could cause a series of hazards to consumers. Here, VAL was designed to be conjugated with bovine serum protein to prepare immunogen. A highly sensitive monoclonal antibody that recognized both VAL and TIA has been successfully produced. Moreover, an immunochromatographic strip assay for rapidly screening VAL and TIA in porcine liver was established with visual detection limits (cutoff values) of 50 and 25 ng/g, respectively. The IC50 values calculated from the equation of the standard curve were 6.06 and 3.45 ng/g and the limits of detection were 0.96 and 0.29 ng/g for VAL and TIA. According to the recovery experiment results, the test strip exhibited acceptable accuracy and precision. Generally, the proposed strip provided a practical tool for the detection of VAL and TIA. Practical Application We produced a highly sensitive monoclonal antibody and developed an immunoassay strip for simultaneously monitoring TIA and VAL. Additionally it was preliminarily confirmed that the rapid detection tool was suitable for screening TIA and VAL in porcine liver.

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Wolbachia Endosymbionts as Treatment Targets for Filarial Diseases

Hübner¹,

Pfarr²,

Hoerauf³

2022

Human and Animal Filariases

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Boron-Pleuromutilins as Anti-Wolbachia Agents with Potential for Treatment of Onchocerciasis and Lymphatic Filariasis

Cited by 38 publications

References 53 publications

In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis

In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis

A highly sensitive monoclonal antibody−based paper sensor for simultaneously detecting valnemulin and tiamulin in porcine liver

Wolbachia Endosymbionts as Treatment Targets for Filarial Diseases

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