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

Ascending Chlamydia trachomatis infection causes functional damage to the fallopian tubes, which may lead to ectopic pregnancy and infertility in women. Treatment failures using the standard regimens of doxycycline and azithromycin have been observed. We tested the polyketide-derived α-pyrone antibiotic Corallopyronin A (CorA) that inhibits the bacterial DNA dependent RNA polymerase and has strong activity against various extracellular and some intracellular bacteria. Extensive testing in cell culture infection models and in an ex vivo human fallopian tube model under different oxygen concentrations was performed to assess the anti-chlamydial efficacy of CorA at physiological conditions. CorA showed high efficacy against C. trachomatis (MICN/H: 0.5 μg/mL for serovar D and L2), C. muridarum (MICN/H: 0.5 μg/mL), and C. pneumoniae (MICN/H: 1 μg/mL) under normoxic (N) and hypoxic (H) conditions. Recoverable inclusion forming units were significantly lower already at 0.25 μg/mL for all tested chlamydiae. CorA at a concentration of 1 μg/mL was also effective against already established C. trachomatis and C. pneumoniae infections (up to 24 h.p.i.) in epithelial cells, while efficacy against C. muridarum was limited to earlier time points. A preliminary study using a C. muridarum genital infection model revealed corresponding limitations in the efficacy. Importantly, in an ex vivo human fallopian tube model, the growth of C. trachomatis was significantly inhibited by CorA at concentrations of 1–2 μg/mL under normoxic and hypoxic conditions. The overall high efficacies of CorA against C. trachomatis in cell culture and an ex vivo human fallopian tube model under physiological oxygen concentrations qualifies this drug as a candidate that should be further investigated

Hearing rehabilitation and microbial shift after middle ear surgery with Vibrant Soundbridge in patients with chronic otitis media

IntroductionPatients with otitis media (OM) encounter significant functional hearing impairment with conductive, or a combined hearing loss and long-term sequelae involving impaired speech/language development in children, reduced academic achievement and irreversible disorders of middle and inner ear requiring a long time therapy and/or multiple surgeries. In its persistent chronic form, Otitis media (COM) can often only be treated by undergoing ear surgery for hearing restoration. The persistent inflammatory reaction plays a major role, often caused by multi-resistant pathogens in the ear. Herein, we present outcomes of patients implanted with currently the only FDA approved active Middle Ear Implant Vibrant Soundbridge (VSB), suffering from persistent COM.MethodsThe study enrolled 42 patients, treated by performing middle ear (ME) surgery to different extents and implanted with the VSB to various structures in the ME. Included were 17 children and 25 adults that had recurrent and/or persisting OM and significant hearing loss. Preoperative and postoperative patients' audiometric data were evaluated and the benefit with VSB assessed using the Glasgow Benefit Inventory for adults and pediatric cohorts. The microbial spectrum of pathogens was assessed before and after surgery, exploring the colonization of the otopathogens, as well as the intestinal microbiome from individually burdened patients.ResultsThe mean functional gain is 29.7 dB HL (range from 10 to 56.2 dB HL) with a significant improvement in speech intelligibility in quiet. Following VSB implantation, no significant differences in coupling were observed at low complication rates. Postoperatively patients showed significantly increased benefit with VSB compared to the untreated situation, including less otorrhea, pain, medical visits, and medication intake, with no recurrent OM and significant bacterial shift in otopathogens. The analysis of the intestinal microbiome displayed a high abundance of bacterial strains that might be linked to chronic and persistent inflammation.ConclusionsFunctional ear surgery including rehabilitation with a VSB in patients suffering from COM present to be safe and effective. The successful acceptance accompanied by the improved audiological performance resulted in significant benefit with VSB, with a shift in the ear pathogens and altered microbiome and thus is a great opportunity to be treated

Microbiota-based analysis reveals specific bacterial traits and a novel strategy for the diagnosis of infectious infertility

<div><p>Tubal factor infertility (TFI) accounts for more than 30% of the cases of female infertility and mostly resides from an inflammatory process triggered by an infection. Clinical appearances largely differ, and very often infections are not recognized or remain completely asymptomatic over time. Here, we characterized the microbial pattern in females diagnosed with infectious infertility (ININF) in comparison to females with non-infectious infertility (nININF), female sex workers (FSW) and healthy controls (fertile). Females diagnosed with infectious infertility differed significantly in the seroprevalence of IgG antibodies against the <i>C</i>. <i>trachomatis</i> proteins MOMP, OMP2, CPAF and HSP60 when compared to fertile females. Microbiota analysis using 16S amplicon sequencing of cervical swabs revealed significant differences between ININF and fertile controls in the relative read count of <i>Gardnerella</i> (10.08% <i>vs</i>. 5.43%). Alpha diversity varies among groups, which are characterized by community state types including <i>Lactobacillus</i>-dominated communities in fertile females, an increase in diversity in all the other groups and <i>Gardnerella</i>-dominated communities occurring more often in ININF. While all single parameters did not allow predicting infections as the cause of infertility, including <i>C</i>. <i>trachomatis</i> IgG/IgA status together with 16S rRNA gene analysis of the ten most frequent taxa a total of 93.8% of the females were correctly classified. Further studies are needed to unravel the impact of the cervical microbiota in the pathogenesis of infectious infertility and its potential for identifying females at risk earlier in life.</p></div

Self-reported questionnaire on previous infections.

<p>Including human Papillomavirus (HPV), <i>N</i>. <i>gonorrhoeae</i>, Herpes simplex virus (HSV), <i>Treponema pallidum</i>, Hepatitis B/C and HIV (Fisher´s exact test: *p<0.05, **p<0.01).</p

Average relative read count of bacteria and bacterial diversity differ between the study groups.

<p>The relative read count of genera in each study group is displayed (A). Genera are shown if they account for a minimum of one percent in at least one of the groups. An overview of statistical comparisons among taxa can be found in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0191047#pone.0191047.s005" target="_blank">S1 Table</a>. The diversity of each sample was calculated using Simpson´s diversity index and plotted according to the study groups (B; Wilcoxon rank-sum test with Hochberg correction: ***p<0.001). nININF: Non-infectious infertility; ININF: Infectious infertility; FSW: Female sex worker.</p

Results of the diagnostic testing for sexually transmitted infections.

<p>Diagnostics were performed by PCR (A) and conventional bacterial culture (B) from cervical swabs. Serological testing was apllied for IgG (C) and IgA (D) antibodies targeting different epitopes (MOMP, OMP2, TARP, CPAF and HSP60) of <i>C</i>. <i>trachomatis</i> (Fisher´s exact test: *p<0.05, **p<0.01, ***p<0.001). GBS: Group B <i>Streptococcus</i>.</p

Metagenomic analysis using PICRUSt prediction of the metagenome based on normalized 16S rRNA gene sequences.

<p>Complete linkage clustering of samples based on predicted metagenomes and assignment of CSTs and study groups. The predicted metagenome clustering shows high concordance with the CST assignment. Lcr: <i>L</i>. <i>crispatus</i>-dominated CST; Lin: <i>L</i>. <i>iners</i>-dominated CST; Lga: <i>L</i>. <i>gasseri</i>-dominated CST; Gva: <i>G</i>. <i>vaginalis</i>-dominated CST; div: diverse communities. nININF: Non-infectious infertility; ININF: Infectious infertility; FSW: Female sex worker.</p