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Background Bacterial vaginosis (BV) is the most common vaginal syndrome among women in their reproductive years. It is associated with an increased risk of acquiring sexually transmitted infections and complications like preterm labor. BV is characterized by a high recurrence rate for which biofilms frequently found on vaginal epithelial cells may be a reason. Results Here, we report a controlled randomized clinical trial that tested the safety and effectiveness of a newly developed pessary containing an amphoteric tenside (WO3191) to disrupt biofilms after metronidazole treatment of BV. Pessaries containing lactic acid were provided to the control group, and microbial community composition was determined via Illumina sequencing of the V1-V2 region of the 16S rRNA gene. The most common community state type (CST) in healthy women was characterized by Lactobacillus crispatus. In BV, diversity was high with communities dominated by either Lactobacillus iners, Prevotella bivia , Sneathia amnii , or Prevotella amnii. Women with BV and proven biofilms had an increased abundance of Sneathia sanguinegens and a decreased abundance of Gardnerella vaginalis. Following metronidazole treatment, clinical symptoms cleared, Nugent score shifted to Lactobacillus dominance, biofilms disappeared, and diversity (Shannon index) was reduced in most women. Most of the patients responding to therapy exhibited a L. iners CST. Treatment with WO 3191 reduced biofilms but did not prevent recurrence. Women with high diversity after antibiotic treatment were more likely to develop recurrence. Conclusions Stabilizing the low diversity healthy flora by promoting growth of health-associated Lactobacillus sp. such as L. crispatus may be beneficial for long-term female health. Trial registration ClinicalTrials.gov NCT02687789

Background International recommendations in favor of screening for vaginal infection in pregnancy are based on heterogeneous criteria. In most developed countries, the diagnosis of bacterial vaginosis is only recommended for women with high-risk of preterm birth. The Nugent score is currently used, but molecular quantification tools have recently been reported with a high sensitivity and specificity. Their value for reducing preterm birth rates and related complications remains unexplored. This trial was designed to assess the cost-effectiveness of a systematic screen-and-treat program based on a point-of-care technique for rapid molecular diagnosis, immediately followed by an appropriate antibiotic treatment, to detect the presence of abnormal vaginal flora (specifically, Atopobium vaginae and Gardnerella vaginalis ) before 20 weeks of gestation in pregnant women in France. We hypothesized that this program would translate into significant reductions in both the rate of preterm births and the medical costs associated with preterm birth. Methods/Design A multicenter, open-label randomized controlled trial (RCT) will be conducted in which 20 French obstetrics and gynecology centers will recruit eligible pregnant women at less than 20 weeks gestation with singleton pregnancy and with a low-risk factor for preterm birth. Interventions will include a) an experimental group that will receive a systematic rapid screen-and-treat program from a point-of-care analysis using a molecular quantification method and b) a control group that will receive usual care management. Randomization will be in a 1:1 allocation ratio. The primary endpoint that will be assessed over a period of 12 months will be the incremental cost-effectiveness ratio (ICER) expressed as cost per avoided preterm birth before 37 weeks. Secondary endpoints will include ICER per avoided preterm birth before 24, 28 and 32 weeks, obstetrical outcomes, neonatal outcomes, rates of treatment failure and recurrence episodes for positive women. Uncertainty surrounding these estimates will be addressed using nonparametric bootstrapping and represented using cost-effectiveness acceptability curves. A total of 6,800 pregnant women will be included. Discussion This appropriate randomized controlled design will provide insight into the cost-effectiveness and therefore the potential cost savings of a rapid screen-and-treat strategy for molecular abnormal vaginal flora in pregnant women. National and international recommendations could be updated based on the findings of this study. Trial registration ClinicalTrials.gov: NCT02288832 (registration date: 30 October 2014); Eudract: 2014-001559-22.

Practitioners and patients alike widely recognize the limitations of current therapeutic approaches to the treatment of bacterial vaginosis (BV). Options remain extremely limited, and our inability to prevent the frequently, often relentless symptomatic recurrences of BV and to reduce serious sequelae such as preterm delivery, remains an acknowledged but unresolved shortcoming. Our incomplete understanding of the pathophysiology of this unique form of vaginal dysbiosis has been a significant impediment to developing optimal treatment and prevention approaches. New drugs have not been forthcoming and are not likely to be available in the immediate future; hence, reliance on the optimal use of available agents has become essential as improvised often unproven regimens are implemented. In this review, we will explore the limitations of currently recommended therapies, with a particular focus on the contribution of reinfection and pathogen persistence to BV recurrence, and the development of interventions that target these mechanisms. Ultimately, to achieve sustained cure and effectiveness against BV-associated sequelae, it is possible that we will need approaches that combine antimicrobials with biofilm-disrupting agents and partner treatments in those at risk of reinfection.

Bacterial vaginosis is a condition associated with adverse reproductive outcomes and characterized by a shift from a Lactobacillus -dominant vaginal microbiota to a polymicrobial microbiota, consistently colonized by strains of Gardnerella vaginalis . Metronidazole is the first-line treatment; however, treatment failure and recurrence rates remain high. To understand complex interactions between Gardnerella vaginalis and Lactobacillus involved in efficacy, here we develop an ordinary differential equation model that predicts bacterial growth as a function of metronidazole uptake, sensitivity, and metabolism. The model shows that a critical factor in efficacy is Lactobacillus sequestration of metronidazole, and efficacy decreases when the relative abundance of Lactobacillus is higher pre-treatment. We validate results in Gardnerella and Lactobacillus co-cultures, and in two clinical cohorts, finding women with recurrence have significantly higher pre-treatment levels of Lactobacillus relative to bacterial vaginosis–associated bacteria. Overall results provide mechanistic insight into how personalized differences in microbial communities influence vaginal antibiotic efficacy. Bacterial vaginosis (BV) is typically caused by a shift in the vaginal microbiota from a Lactobacillus -dominant community to one colonised by strains of Gardenerella vaginalis and treatment with the antibiotic metronidazole (MNZ) often results in failure and recurrence. Here, the authors use modelling and in vitro assays to show that sequestration of MNZ by Lactobacillus is critical in reducing efficacy and women with a higher pre-treatment Lactobacillus / Gardnerella ratio are more likely to recur.

Gardnerella vaginalis is the most frequently identified bacterium in approximately 95% of bacterial vaginosis (BV) cases. This species often exhibits resistance to multiple antibiotics, posing challenges for treatment. Therefore, there is an urgent need to develop and explore alternative therapeutic strategies for managing bacterial vaginosis. The objective of this study was to identify virulence factors and potential drug targets against Gardnerella vaginalis by utilizing in silico methods, including subtractive and comparative genomics. These methods enabled the systematic comparison of genetic sequences to pinpoint specific features unique to G. vaginalis and crucial for its pathogenicity, which could then inform the development of targeted therapeutic strategies. The analysis of the pathogen's proteomic data aimed to identify proteins that fulfilled specific criteria. These included being non-homologous to human proteins, essential for bacterial survival, amenable to drug targeting, involved in virulence, and contributing to antibiotic resistance. Following these analyses and an extensive literature review, the phospho-2-dehydro-3-deoxyheptonate aldolase enzyme emerged as a promising drug target. To deepen our understanding of the biological function of the identified protein, comprehensive protein structural modeling, validation studies, and network topology analyses were conducted. The subsequent structural analysis, encompassing modeling, validation, and network topology assessment, is aimed at further characterizing the protein. Using a library of around 9,000 FDA-approved compounds from the DrugBank database, a virtual screening was conducted to identify potential compounds that could effectively target the proposed drug target. This approach facilitated the evaluation of existing drugs for their ability to inhibit the target, potentially offering an efficient pathway for developing new treatments against the pathogen. Leveraging the established efficacy, safety, pharmacokinetics, and pharmacodynamics of these compounds, the study suggests repurposing them for Gardnerella vaginalis infections. Among the screened compounds, five specific agents—DB03332, DB07452, DB01262, DB02076, and DB00727—were identified as cost-effective therapeutic options for treating infections related to Gardnerella vaginalis . These compounds were selected based on their efficacy in targeting the pathogen while maintaining economic feasibility. While the results indicate potential efficacy in treating infections caused by the pathogen, further experimental studies are essential to validate these findings.

Bacterial vaginosis (BV) is caused by vaginal microbiome dysbiosis, when beneficial Lactobacillus species are no longer dominant and are replaced by harmful anaerobic bacteria such as Gardnerella vaginalis. In Caribbean cultures, women use plants topically, such as Argemone mexicana , to treat several vaginal infections, including BV. There has been little research into how traditional botanical extracts affect the vaginal microbiota, especially as these extracts are often prepared in different ways for the same condition. This study aims to evaluate the effect of botanical preparations using an in vitro co-culture assay with beneficial Lactobacillus species and BV-causing Gardnerella vaginalis . This is an application of an in vitro co-culture assay to assess the effect of botanical preparations on the vaginal microbiota. We hypothesized that variations in the chemical composition of these preparations would affect the composition of vaginal microbiota. Argemone mexicana extractions were tested using an in vitro co-culture method with Gardnerella vaginalis and one of three vaginal Lactobacillus species and evaluated by UPLC-qToF-MS for metabolomic chemical analysis. Aqueous extractions that did not have significant antibacterial effect compared to the control in monoculture suppressed the growth of Gardnerella vaginalis in co-culture with Lactobacillus , supporting the traditional Dominican use of this plant. These results are likely related to the presence of berberine and polysaccharides in the aqueous extractions.

Objective Vaginal lactobacilli play a crucial role in inhibiting bacteria such as Gardnerella vaginalis ( G. vaginalis ), a key contributor to dysbiosis and bacterial vaginosis. We aimed to compare the inhibitory effects of Lactobacillus cell-free supernatants on G. vaginalis growth with those observed in Lactobacillus - G. vaginalis coculture, an experimental setup that more closely mimics in vivo conditions. Results To identify the optimal medium for coculture experiments, MRS broth and NYC-III broth were compared. NYC-III significantly enhanced the growth of G. vaginalis and four of the five tested Lactobacillus strains. We then developed a direct quantitative PCR (qPCR) method that allowed us to specifically measure G. vaginalis genome concentrations in cocultures with Lactobacillus . This direct qPCR did not require DNA extraction and had a 4,096-fold dynamic range. We then assessed the inhibition of G. vaginalis growth by Lactobacillus cell-free supernatants in G. vaginalis cultures by measuring optical density and the Lactobacillus -mediated inhibition in cocultures by the G. vaginalis specific direct qPCR. The two measurement methods showed different levels of inhibitory activity for two of the five Lactobacillus strains tested. These findings suggest that coculture experiments should be conducted in place of, or in addition to, supernatant-based inhibitory assays.

Bacterial vaginosis (BV), primarily attributed to Gardnerella vaginalis , poses significant challenges due to antibiotic resistance and suboptimal treatment outcomes. This study presents an integrated approach to identify potential drug targets and screen compounds against this bacterium by leveraging a computational methodology. Subtractive proteomics of the reference strain ASM286196v1/UMB0386 (assembly accession: GCA_002861965.1) facilitated the prioritization of proteins with essential bacterial functions and pathways as potential drug targets. We selected 3-deoxy-7-phosphoheptulonate synthase ( aroG gene product; also known as DAHP synthase) for downstream analysis. Molecular docking was employed in PyRx (AutoDock Vina) to predict binding affinities between aroG inhibitors from the ZINC database and 3-deoxy-7-phosphoheptulonate synthase. Molecular dynamics simulations of 100 ns, using GROMACS, validated the stability of drug-target interactions. Additionally, ADMET profiling aided in the selection of compounds with favorable pharmacokinetic properties and safety profile for human hosts. PBPK profiling showed that ZINC98088375 had the highest bioavailability and efficient systemic circulation. Conversely, ZINC5113880 demonstrated the lowest absorption rate (39.661%). Moreover, cirrhosis, steatosis, and renal impairment appeared to influence blood concentration of the drug, impacting bioavailability. The integrative –omics approach utilized in this study underscores the potential of computer-aided drug design and offers a rational strategy for targeted inhibitor discovery against G. vaginalis. The strategy is an attempt to address the limitations of current BV treatments, including antibiotic resistance, and pave way for the development of safer and more effective therapeutics.

Background Bacterial vaginosis (BV) affects 20–50% of reproductive-age female patients annually, arising when opportunistic pathogens outcompete healthy vaginal flora. Many patients fail to resolve symptoms with a course of metronidazole, the current first-line treatment for BV. Our study was designed to identify genomic variation associated with metronidazole resistance among strains of Gardnerella vaginalis spp. (GV), a genus of biogenic-amine-producing bacteria closely associated with BV pathogenesis, for the development of a companion molecular diagnostic. Methods Whole-genome sequencing and comparative genomic metrics, including average nucleotide identity and GC content, were performed on a diverse set of 129 GV genomes to generate data for detailed taxonomic analyses. Pangenomic analyses were employed to construct a phylogenetic tree and cluster highly related strains within genospecies. G. vaginalis spp. clinical isolates within our collection were subjected to plate-based minimum inhibitory concentration (MIC) testing of metronidazole ( n  = 60) and clindamycin ( n  = 63). DECIPHER and MAFFT were used to identify genospecies-specific primers associated with antibiotic-resistance phenotypes. PCR-based analyses with these primers were used to confirm their specificity for the relevant genospecies. Results Eleven distinct genospecies based on standard ANI criteria were identified among the GV strains in our collection. Metronidazole MIC testing revealed six genospecies within a closely related phylogenetic clade contained only highly metronidazole-resistant strains (MIC ≥ 32 µg/mL) and suggested at least two mechanisms of metronidazole resistance within the eleven GV genospecies. All strains within the six highly metronidazole-resistant genospecies displayed susceptibility to clinically relevant clindamycin concentrations (MIC ≤ 2 µg/mL). A PCR-based molecular diagnostic assay was developed to distinguish between members of the metronidazole-resistant and mixed-response genospecies, which should be useful for determining the clade membership of various GV strains and could assist in the selection of appropriate antibiotic therapies for BV cases. Conclusions This study provides comparative genomic and phylogenetic evidence for eleven distinct genospecies within the genus Gardnerella vaginalis spp., and identifies genospecies-specific responses to metronidazole, the first-line treatment for BV. A companion molecular diagnostic assay was developed that is capable of identifying essentially all highly metronidazole-resistant strains that phylogenetically cluster together within the GV genospecies, which is informative for antibiotic treatment options.

Background Worldwide, bacterial vaginosis (BV) is the most common vaginal disorder. It is associated with risk for preterm birth and HIV infection. The etiology of the condition has been debated for nearly half a century and the lack of knowledge about its cause and progression has stymied efforts to improve therapy and prevention. Gardnerella vaginalis was originally identified as the causative agent, but subsequent findings that it is commonly isolated from seemingly healthy women cast doubt on this claim. Recent studies shedding light on the virulence properties of G. vaginalis , however, have drawn the species back into the spotlight. Results In this study, we sequenced the genomes of a strain of G. vaginalis from a healthy woman, and one from a woman with bacterial vaginosis. Comparative analysis of the genomes revealed significant divergence and in vitro studies indicated disparities in the virulence potential of the two strains. The commensal isolate exhibited reduced cytotoxicity and yet the cytolysin proteins encoded by the two strains were nearly identical, differing at a single amino acid, and were transcribed at similar levels. The BV-associated strain encoded a different variant of a biofilm associated protein gene and demonstrated greater adherence, aggregation, and biofilm formation. Using filters with different pore sizes, we found that direct contact between the bacteria and epithelial cells is required for cytotoxicity. Conclusions The results indicated that contact is required for cytotoxicity and suggested that reduced cytotoxicity in the commensal isolate could be due to impaired adherence. This study outlines two distinct genotypic variants of G. vaginalis , one apparently commensal and one pathogenic, and presents evidence for disparate virulence potentials.