Orientia tsutsugamushi Is Highly Susceptible to the RNA Polymerase Switch Region Inhibitor Corallopyronin A In Vitro and In Vivo

Abstract

Scrub typhus is a potentially lethal infection caused by the obligate intracellular bacterium Reports on the emergence of doxycycline-resistant strains highlight the urgent need to develop novel antiinfectives against scrub typhus. Corallopyronin A (CorA) is a novel α-pyrone compound synthesized by the myxobacterium that was characterized as a noncompetitive inhibitor of the switch region of the bacterial RNA polymerase (RNAP). We investigated the antimicrobial action of CorA against the human-pathogenic Karp strain of and The MIC of CorA against was remarkably low (0.0078 μg/ml), 16-fold lower than that against In the lethal intraperitoneal mouse infection model, a minimum daily dose of 100 μg CorA protected 100% of infected mice. Two days of treatment were sufficient to confer protection. In contrast to BALB/c mice, SCID mice succumbed to the infection despite treatment with CorA or tetracycline, suggesting that antimicrobial treatment required synergistic action of the adaptive immune response. Similar to tetracycline, CorA did not prevent latent infection of However, latency was not caused by acquisition of antimicrobial resistance, since reisolated from latently infected BALB/c mice remained fully susceptible to CorA. No mutations were found in the CorA-binding regions of the β and β' RNAP subunit genes and Inhibition of the RNAP switch region of by CorA is therefore a novel and highly potent target for antimicrobial therapy for scrub typhus.

Elaborations on Corallopyronin A as a Novel Treatment Strategy Against Genital Chlamydial Infections

“…CorA is a promising drug against other intracellular pathogens, such as Wolbachia endobacteria and O. tsutsugamushi (Schiefer et al, 2012; Kock et al, 2018) and, therefore, its efficacy against Chlamydia spp. was determined.…”

“…The usage of various animal models in chlamydial infection is broadly accepted, and has successfully been applied in investigations on CorA efficacy against other intracellular bacteria in mice (Schiefer et al, 2012; Kock et al, 2018). Hence, we were interested in the outcome of CorA treatment in an acute C. muridarum mouse infection model in comparison to standard doxycycline treatment.…”

“…Thus, this antimicrobial is specific to prokaryotic RNAP (Irschik et al, 1985; Campbell et al, 2001; Belogurov et al, 2009). While CorA was originally described to inhibit the growth of Gram-positive bacteria (MIC value: between 0.1 and 10 μg/mL) (Irschik et al, 1985), it has recently been shown that it is also highly active against Gram-negative intracellular O. tsutsugamushi (Kock et al, 2018) and Wolbachia endobacteria in vitro and in vivo (Schiefer et al, 2012). The structure and preponderance of efflux pumps of many Gram-negative bacteria seems to be a barrier to CorA (Irschik et al, 1985).…”

“…In the case of the treatment of O. tsutsugamushi the treatment duration is comparable to our setting. However, treatment was applied directly at the site of infection (Kock et al, 2018) and is thus not comparable to our model.…”

“…The antimicrobial efficacy of CorA has been shown mainly for Gram-positive bacteria (Irschik et al, 1985). However, it also eradicates the Gram-negative intracellular bacteria Wolbachia (Schiefer et al, 2012) and Orientia tsutsugamushi (Kock et al, 2018) in vitro and in vivo . We have shown that CorA is a potent antibiotic for the eradication of rifampicin-resistant C. trachomatis serovar L2 in vitro (Shima et al, 2018).…”