Discovery of kirromycins with anti- wolbachia activity from streptomyces sp. CB00686

Zhengren Xu, Shi-Ming Fang, Malina A. Bakowski, Mostafa E. Rateb, Dong Yang, Xiangcheng Zhu, Yong Huang, Li-Xing Zhao, Yi Jiang, Yanwen Duan, Mitchell V. Hull, Case W. McNamara, Ben Shen

Research output: Contribution to journalArticle

Abstract

Lymphatic filariasis and onchocerciasis diseases caused by filarial parasite infections can lead to profound disability and affect millions of people worldwide. Standard mass drug administration campaigns require repetitive delivery of anthelmintics for years to temporarily block parasite transmission but do not cure infection because long-lived adult worms survive the treatment. Depletion of the endosymbiont Wolbachia, present in most filarial nematode species, results in death of adult worms and therefore represents a promising target for the treatment of filariasis. Here, we used a high-content imaging assay to screen the pure compounds collection of the natural products library at The Scripps Research Institute for anti- Wolbachia activity, leading to the identification of kirromycin B (1) as a lead candidate. Two additional congeners, kirromycin (2) and kirromycin C (3), were isolated and characterized from the same producing strain Streptomyces sp. CB00686. All three kirromycin congeners depleted Wolbachia in LDW1 Drosophila cells in vitro with half-maximal inhibitory concentrations (IC50) in nanomolar range, while doxycycline, a registered drug with anti- Wolbachia activity, showed lower activity with an IC50 of 152 ± 55 nM. Furthermore, 1-3 eliminated the Wolbachia endosymbiont in Brugia pahangi ovaries ex vivo with higher efficiency (65%-90%) at 1 μM than that of doxycycline (50%). No cytotoxicity against HEK293T and HepG2 mammalian cells was observed with 1-3 at the highest concentration (40 μM) used in the assay. These results suggest kirromycin is an effective lead scaffold, further exploration of which could potentially lead to the development of novel treatments for filarial nematode infections.

Original languageEnglish
Pages (from-to)1174-1182
Number of pages9
JournalACS Chemical Biology
Volume14
Issue number6
DOIs
Publication statusPublished - 10 May 2019
Externally publishedYes

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Wolbachia
Streptomyces
Doxycycline
Inhibitory Concentration 50
Brugia pahangi
Filarial Elephantiasis
Nematode Infections
Onchocerciasis
Filariasis
Parasitic Diseases
Anthelmintics
Hep G2 Cells
Biological Products
Pharmaceutical Preparations
Drosophila
Ovary
Parasites
mocimycin
Infection

Cite this

Xu, Zhengren ; Fang, Shi-Ming ; Bakowski, Malina A. ; Rateb, Mostafa E. ; Yang, Dong ; Zhu, Xiangcheng ; Huang, Yong ; Zhao, Li-Xing ; Jiang, Yi ; Duan, Yanwen ; Hull, Mitchell V. ; McNamara, Case W. ; Shen, Ben. / Discovery of kirromycins with anti- wolbachia activity from streptomyces sp. CB00686. In: ACS Chemical Biology. 2019 ; Vol. 14, No. 6. pp. 1174-1182.
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title = "Discovery of kirromycins with anti- wolbachia activity from streptomyces sp. CB00686",
abstract = "Lymphatic filariasis and onchocerciasis diseases caused by filarial parasite infections can lead to profound disability and affect millions of people worldwide. Standard mass drug administration campaigns require repetitive delivery of anthelmintics for years to temporarily block parasite transmission but do not cure infection because long-lived adult worms survive the treatment. Depletion of the endosymbiont Wolbachia, present in most filarial nematode species, results in death of adult worms and therefore represents a promising target for the treatment of filariasis. Here, we used a high-content imaging assay to screen the pure compounds collection of the natural products library at The Scripps Research Institute for anti- Wolbachia activity, leading to the identification of kirromycin B (1) as a lead candidate. Two additional congeners, kirromycin (2) and kirromycin C (3), were isolated and characterized from the same producing strain Streptomyces sp. CB00686. All three kirromycin congeners depleted Wolbachia in LDW1 Drosophila cells in vitro with half-maximal inhibitory concentrations (IC50) in nanomolar range, while doxycycline, a registered drug with anti- Wolbachia activity, showed lower activity with an IC50 of 152 ± 55 nM. Furthermore, 1-3 eliminated the Wolbachia endosymbiont in Brugia pahangi ovaries ex vivo with higher efficiency (65{\%}-90{\%}) at 1 μM than that of doxycycline (50{\%}). No cytotoxicity against HEK293T and HepG2 mammalian cells was observed with 1-3 at the highest concentration (40 μM) used in the assay. These results suggest kirromycin is an effective lead scaffold, further exploration of which could potentially lead to the development of novel treatments for filarial nematode infections.",
author = "Zhengren Xu and Shi-Ming Fang and Bakowski, {Malina A.} and Rateb, {Mostafa E.} and Dong Yang and Xiangcheng Zhu and Yong Huang and Li-Xing Zhao and Yi Jiang and Yanwen Duan and Hull, {Mitchell V.} and McNamara, {Case W.} and Ben Shen",
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doi = "10.1021/acschembio.9b00086",
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Xu, Z, Fang, S-M, Bakowski, MA, Rateb, ME, Yang, D, Zhu, X, Huang, Y, Zhao, L-X, Jiang, Y, Duan, Y, Hull, MV, McNamara, CW & Shen, B 2019, 'Discovery of kirromycins with anti- wolbachia activity from streptomyces sp. CB00686' ACS Chemical Biology, vol. 14, no. 6, pp. 1174-1182. https://doi.org/10.1021/acschembio.9b00086

Discovery of kirromycins with anti- wolbachia activity from streptomyces sp. CB00686. / Xu, Zhengren; Fang, Shi-Ming; Bakowski, Malina A.; Rateb, Mostafa E.; Yang, Dong; Zhu, Xiangcheng; Huang, Yong; Zhao, Li-Xing; Jiang, Yi; Duan, Yanwen; Hull, Mitchell V.; McNamara, Case W.; Shen, Ben.

In: ACS Chemical Biology, Vol. 14, No. 6, 10.05.2019, p. 1174-1182.

Research output: Contribution to journalArticle

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T1 - Discovery of kirromycins with anti- wolbachia activity from streptomyces sp. CB00686

AU - Xu, Zhengren

AU - Fang, Shi-Ming

AU - Bakowski, Malina A.

AU - Rateb, Mostafa E.

AU - Yang, Dong

AU - Zhu, Xiangcheng

AU - Huang, Yong

AU - Zhao, Li-Xing

AU - Jiang, Yi

AU - Duan, Yanwen

AU - Hull, Mitchell V.

AU - McNamara, Case W.

AU - Shen, Ben

PY - 2019/5/10

Y1 - 2019/5/10

N2 - Lymphatic filariasis and onchocerciasis diseases caused by filarial parasite infections can lead to profound disability and affect millions of people worldwide. Standard mass drug administration campaigns require repetitive delivery of anthelmintics for years to temporarily block parasite transmission but do not cure infection because long-lived adult worms survive the treatment. Depletion of the endosymbiont Wolbachia, present in most filarial nematode species, results in death of adult worms and therefore represents a promising target for the treatment of filariasis. Here, we used a high-content imaging assay to screen the pure compounds collection of the natural products library at The Scripps Research Institute for anti- Wolbachia activity, leading to the identification of kirromycin B (1) as a lead candidate. Two additional congeners, kirromycin (2) and kirromycin C (3), were isolated and characterized from the same producing strain Streptomyces sp. CB00686. All three kirromycin congeners depleted Wolbachia in LDW1 Drosophila cells in vitro with half-maximal inhibitory concentrations (IC50) in nanomolar range, while doxycycline, a registered drug with anti- Wolbachia activity, showed lower activity with an IC50 of 152 ± 55 nM. Furthermore, 1-3 eliminated the Wolbachia endosymbiont in Brugia pahangi ovaries ex vivo with higher efficiency (65%-90%) at 1 μM than that of doxycycline (50%). No cytotoxicity against HEK293T and HepG2 mammalian cells was observed with 1-3 at the highest concentration (40 μM) used in the assay. These results suggest kirromycin is an effective lead scaffold, further exploration of which could potentially lead to the development of novel treatments for filarial nematode infections.

AB - Lymphatic filariasis and onchocerciasis diseases caused by filarial parasite infections can lead to profound disability and affect millions of people worldwide. Standard mass drug administration campaigns require repetitive delivery of anthelmintics for years to temporarily block parasite transmission but do not cure infection because long-lived adult worms survive the treatment. Depletion of the endosymbiont Wolbachia, present in most filarial nematode species, results in death of adult worms and therefore represents a promising target for the treatment of filariasis. Here, we used a high-content imaging assay to screen the pure compounds collection of the natural products library at The Scripps Research Institute for anti- Wolbachia activity, leading to the identification of kirromycin B (1) as a lead candidate. Two additional congeners, kirromycin (2) and kirromycin C (3), were isolated and characterized from the same producing strain Streptomyces sp. CB00686. All three kirromycin congeners depleted Wolbachia in LDW1 Drosophila cells in vitro with half-maximal inhibitory concentrations (IC50) in nanomolar range, while doxycycline, a registered drug with anti- Wolbachia activity, showed lower activity with an IC50 of 152 ± 55 nM. Furthermore, 1-3 eliminated the Wolbachia endosymbiont in Brugia pahangi ovaries ex vivo with higher efficiency (65%-90%) at 1 μM than that of doxycycline (50%). No cytotoxicity against HEK293T and HepG2 mammalian cells was observed with 1-3 at the highest concentration (40 μM) used in the assay. These results suggest kirromycin is an effective lead scaffold, further exploration of which could potentially lead to the development of novel treatments for filarial nematode infections.

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