Chlamydia Serine Protease Inhibitor, targeting HtrA, as a New Treatment for Koala Chlamydia infection

Abstract

The koala, an iconic marsupial native to Australia, is a threatened species in many parts of the country. One major factor in the decline is disease caused by infection with Chlamydia. Current therapeutic strategies to treat chlamydiosis in the koala are limited. This study examines the effectiveness of an inhibitor, JO146, which targets the HtrA serine protease for treatment of C. pecorum and C. pneumoniae in vitro and ex vivo with the aim of developing a novel therapeutic for koala Chlamydia infections. Clinical isolates from koalas were examined for their susceptibility to JO146. In vitro studies demonstrated that treatment with JO146 during the mid-replicative phase of C. pecorum or C. pneumoniae infections resulted in a significant loss of infectious progeny. Ex vivo primary koala tissue cultures were used to demonstrate the efficacy of JO146 and the non-toxic nature of this compound on peripheral blood mononuclear cells and primary cell lines established from koala tissues collected at necropsy. Our results suggest that inhibition of the serine protease HtrA could be a novel treatment strategy for chlamydiosis in koalas.

Chlamydia pecorum gastrointestinal tract infection associations with urogenital tract infections in the koala (Phascolarctos cinereus)

“…pecorum genomic DNA targeting a 204 bp fragment of the 16S rRNA gene [ 36 ]. Quantification was performed by plotting the crossing points against a standard curve produced using a serial dilution of known standards from 1 x 10 6 to 1 x 10 2 copies/μL [ 37 ]. To determine the genotype of the infecting strain, we amplified a 359 bp region of the C .…”

Extracellular HtrA serine proteases: An emerging new strategy in bacterial pathogenesis

“…The experiments proved the effectiveness of the compound when added to the midreplicative phase of chlamydial developmental cycle without obvious toxicity in the human, mouse, or koala cells (Gloeckl et al, 2013;Lawrence et al, 2016). Moreover, JO146 was lethal against numerous Chlamydia spp., including Chlamydia trachomatis , Chlamydia pneumonia, and Chlamydophila pecorum (Lawrence et al, 2016).…”

“…The experiments proved the effectiveness of the compound when added to the midreplicative phase of chlamydial developmental cycle without obvious toxicity in the human, mouse, or koala cells (Gloeckl et al, 2013;Lawrence et al, 2016). Moreover, JO146 was lethal against numerous Chlamydia spp., including Chlamydia trachomatis , Chlamydia pneumonia, and Chlamydophila pecorum (Lawrence et al, 2016). The latter two species cause severe infections in koalas (Jackson, White, Giffard, & Timms, 1999), so further optimization of JO146 for better specificity may result in a novel drug to treat chlamydiosis in koalas.…”

Chlamydiae from Down Under: The Curious Cases of Chlamydial Infections in Australia

“…In most cases, chronically diseased animals, animals in poor body condition, or with comorbidities such as KoRV-associated disease are not suitable candidates as antibiotics can be detrimental for the koala s gastrointestinal tract microbiota and in severe cases, can lead to dysbiosis and death [99,108]. Novel compounds, such as a serine protease inhibitor (JO146), that inhibits proteolytic activity of the chlamydial putative virulence factor high temperature requirement A (HtrA) [114], and alternative antibiotic therapy with doxycycline and topical supportive therapy have also been proposed [107].…”