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Ivermectin Inhibits Growth of Chlamydia trachomatis in Epithelial Cells

by Matthew A. Pettengill,Verissa W. Lam,Ikechukwu Ollawa,Camila Marques-da-Silva,David M. Ojcius.

#Ivermectin is currently approved for treatment of both clinical and veterinary infections by nematodes, including Onchocerca cervicalis in horses and Onchocerca volvulus in humans. However, ivermectin has never been shown to be effective against bacterial pathogens. Here we show that ivermectin also inhibits infection of epithelial cells by the bacterial pathogen, #Chlamydia trachomatis, at doses that could be envisioned clinically for sexually-transmitted or ocular infections by Chlamydia.

Avermectins are macrocyclic lactone derivatives which are produced during fermentation of Streptomyces avermectinius, a species of actinomycete isolated from soil samples in Japan. Eight avermectins are produced by S. avermectinius (A1a, A1b, A2a, A2b, B1a, B1b, B2a, and B2b). The A series molecules contain a 5′-methoxyl group, while the B series contain a 5′-hydroxyl group and have more potent anti-parasitic activity [1], [2], [3]. Improved efficacy as a broad-spectrum anti-parasitic was achieved for the B1 compounds by selective hydrogenation utilizing Wilkinson’s catalyst (RhCl(PPh3)3), with the resultant product (22,23-dihydroavermectin B1) being given the name ivermectin [4]. Following considerable success as an anti-helminthic agent in veterinary practice, including use for treatment of Onchocerca cervicalis in horses, ivermectin entered clinical trials for use in humans against Onchocerca volvulus, a nematode which causes onchocerciasis (“river blindness”) [5]. Efficacious use in humans has extended to lymphatic filariasis [6], head-lice infestation [7], and scabies [8]. However, avermectins have not been previously described to have anti-bacterial activity [5].

Here we demonstrate that ivermectin inhibits growth of Chlamydia trachomatis during infection of human cervical epithelial cells, suggesting that avermectins may have previously undescribed anti-bacterial activity against pathogenic obligate intracellular bacteria, potentially via indirect effects on the host-cell.

Chlamydiae are obligate intracellular bacteria which mature through a unique biphasic developmental cycle, infecting as metabolically inert elementary bodies (EBs) and maturing into metabolically active but non-infectious reticulate bodies (RBs), which proliferate before condensing into infectious EBs to complete the cycle [9], [10], [11]. C. trachomatis strains, which are the leading cause of bacterial sexually transmitted disease and first cause of preventable blindness [12], primarily infect mucosal epithelial cells.

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