Cysteine dependence of Lactobacillus iners is a potential therapeutic target for vaginal microbiota modulation

Abstract

Vaginal microbiota composition affects many facets of reproductive health. Lactobacillus inersdominant microbial communities are associated with poorer outcomes, including higher risk of bacterial vaginosis (BV), compared with vaginal microbiota rich in Lactobacillus crispatus.Unfortunately, standard-of-care metronidazole therapy for BV typically results in dominance of L. iners, likely contributing to post-treatment relapse. Here we generate an L. iners isolate collection comprising 34 previously unreported isolates from 14 South African with and without BV and 4 previously unreported isolates from 3 US women and we report an associated genome catalog comprising 1,218 vaginal Lactobacillus isolate genomes and metagenome-assembled genomes (MAGs) from >300 women across four continents. We show that, unlike L. crispatus, L. iners growth is dependent on L-cysteine in vitro and we trace this phenotype to the absence of canonical cysteine biosynthesis pathways and a restricted repertoire of cysteine-related transport mechanisms. We further show cysteine concentrations in cervicovaginal lavage samples correlate with Lactobacillus abundance in vivo and that cystine uptake inhibitors selectively inhibit L. iners growth in vitro. Combining an inhibitor with metronidazole promotes L. crispatus dominance of defined BV-like communities in vitro by suppressing L. iners growth. Our findings enable a better understanding of L. iners biology and suggest candidate treatments to modulate the vaginal microbiota to improve reproductive health for women globally.

Host and Microbiome Interplay Shapes the Vaginal Microenvironment

“…Bloom et al. suggested that cysteine dependence of Lactobacillus iners could be a potential target for vaginal microbiome modulation ( 143 ). In this study, the authors found Lactobacillus iners requires cysteine to grow in vitro and that a cysteine uptake inhibitor selectively inhibits growth of Lactobacillus iners rather than other Lactobacillus species.…”

Assessing the Cervicovaginal Microbiota in the Context of hrHPV Infections: Temporal Dynamics and Therapeutic Strategies

“…The production of inerolysin by L. iners , an enzyme responsible for adhesion, can result in the impairment of the mucus layer and epithelial cells, which can cause microwounds that are susceptible to viral infections ( 66 ). L. iners uses the amino acid cysteine, which is produced in the mucus layer, in its metabolic activities ( 67 ). The disturbance of the cervicovaginal ecosystem by CST III microbiomes can promote immune responses that cause cytotoxic effects in the epithelium and can result in a lower number of antigen-presenting cells ( Fig.…”

“…Lactoferrin has anti-inflammatory and antimicrobial activities as well as sequestrates iron, thus making it unavailable for the metabolism of harmful bacteria ( 120 ). In addition, cysteine inhibitors and the combination of the bacteriocins GasK7B α and β derived from a human intestinal strain of Lactobacillus paragasseri have been recently described as potential CVMTs that could prevent the growth of L. iners and the development of BV, and this could be applied against hrHPV infections, since both have been associated with hrHPV-induced cervical disease ( 67 , 121 ).…”

Vaginal microbiome-host interactions modeled in a human vagina-on-a-chip

“…P. bivia and A. vaginae are prevalent species in Lactobacillus-deficient vaginal microbiota. The two strains used in this study were coresident, isolated from a single participant in the Females Rising Through Education Support and Health study [28].…”