The appearance of sugI mixed loci in three individuals during treatment for MDR-TB, supports the involvement of sugI in Mycobacterium tuberculosis d-cycloserine resistance in vivo.

Anthony, R. M.; Molemans, M.; Akkwerman, O.; Sturkenboom, M. G. G.; Mulder, A.; de Zwaan, R.; van Soolingen, D.; Alffenaar, J.-W.; van Leth, F. C. M.; Ghimire, S.; Yastskevich, N.; Skrahina, A.; Ciobanu, N.; Turcan, N.; Crudu, V.

doi:10.1101/2023.05.30.542839

bioRxiv · 10.1101/2023.05.30.542839

The appearance of sugI mixed loci in three individuals during treatment for MDR-TB, supports the involvement of sugI in Mycobacterium tuberculosis d-cycloserine resistance in vivo.

Anthony, R. M.·Molemans, M.·Akkwerman, O.·Sturkenboom, M. G. G.·Mulder, A.·de Zwaan, R.·van Soolingen, D.·Alffenaar, J.-W.·van Leth, F. C. M.·Ghimire, S.·Yastskevich, N.·Skrahina, A.·Ciobanu, N.·Turcan, N.·Crudu, V.

View original source ↗Export metadata ↓

Abstract

To study the adaptation of multi-drug resistant Mycobacterium tuberculosis (MDR-TB) during treatment patients diagnosed with MDR-TB were recruited into an observational study. Clinical data and M. tuberculosis DNA at diagnosis and between seven days and two months of MDR-TB treatment were collected. The drugs prescribed were recorded. Interpretable WGS data from 118 isolates from 54 participants was obtained (11 in Belarus and 43 in Moldova) and screened for the presence of unfixed single nucleotide polymorphisms (mixed SNPs / loci). This study was performed shortly after the publication of the 2019 WHO consolidated guidelines on drug-resistant tuberculosis treatment. Existing drug supplies and procurement in one country after the switch to the all oral MDR-TB regimen in addition to patient factors, influenced the selection of and exposure to drugs. Confidently mixed SNPs were identified in samples from multiple participants in only five genes (gyrA, pncA, Rv1129c, Rv1148c, and sugI). All other genes with confidently mixed SNPs were identified in isolates from only a single individual. A significant proportion of the participants (52 of 54 participants) received d-cycloserine as part of their initial treatment, most participants who initially received d-cycloserine did not receive bedaquiline in their initial regimen (all at one site). Three different mixed SNPs were identified in sugI gene from a follow up isolate from three participants (P7A, P7T, and Q6stop). Mutations in sugI have previously been reported in spontaneous in vitro d-cycloserine resistant mutants. Alterations in the sugI gene may indicate a sub optimal d-cycloserine containing regimen and potentially be of clinical significance with respect to adaptation to d-cycloserine. Monitoring the accumulation of low frequency escape mutants may help identify regimens insufficiently powerful to block the accumulation of antimicrobial resistance mutants and identify drug(s) at risk of resistance selection.

Explore related subjects

microbiology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Anthony, R. M., Molemans, M., Akkwerman, O., Sturkenboom, M. G. G., Mulder, A., de Zwaan, R., van Soolingen, D., Alffenaar, J.-W., van Leth, F. C. M., Ghimire, S., Yastskevich, N., Skrahina, A., Ciobanu, N., Turcan, N., Crudu, V.. 2023-05-30. The appearance of sugI mixed loci in three individuals during treatment for MDR-TB, supports the involvement of sugI in Mycobacterium tuberculosis d-cycloserine resistance in vivo.. https://doi.org/10.1101/2023.05.30.542839

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

A population-scale landscape of the subgingival microbiome reveals divergent routes to periodontal dysbiosis

Periodontitis is an archetypical mucosal inflammatory disease in which microbiome dysbiosis at the tooth-epithelial interface interacts with host genetic and behavioral risk factors to drive immune-mediated tissue destruction. Although subgingival microbiome compositional shifts are thought to parallel disease severity, microbiome variation at the population-level and its relationship to periodontal clinical phenotypes and disease-modifying factors remain poorly defined. Here, we use unsupervised manifold learning to map the compositional landscape of the subgingival microbiome in 1,355 adults spanning periodontal health to severe periodontitis. We identified eight latent microbiome states organized along a branching continuum from eubiosis to dysbiosis. An intermediate microbial configuration marked ecological destabilization and bifurcation into two distinct periodontitis-associated dysbiotic trajectories, distinguished by links to gingival inflammation and smoking. Although the microbiome trajectories broadly tracked periodontal destruction, a minority of individuals showed discordant microbiome-clinical phenotypes, with some individuals with periodontitis retaining otherwise eubiotic microbiomes enriched for low-abundance pathobionts, while some cases of health or mild disease had highly dysbiotic communities, suggesting distinct host susceptibility. Together, these findings define a population-scale ecological landscape of the subgingival microbiome, reveal divergent trajectories to periodontal dysbiosis, and highlight heterogeneity in the relationship between microbial community structure and clinical disease expression.

microbiology↗

bioRxiv2026

The iron-binding siderophore enterobactin is required for the response of multi-drug resistant Klebsiella pneumoniae to zinc limitation

To persist during infection Klebsiella pneumoniae must overcome nutrient iron and zinc limitation imposed by the host immune system through a process called nutritional immunity. Secreted small molecule siderophores are a major virulence determinant of Klebsiella pneumoniae pathogenesis and are presumed to overcome nutritional immunity by binding iron for bacterial acquisition. In this work, we set out to identify how a multi-drug resistant K. pneumoniae grows in zinc limited environments. Using unbiased transcriptomics, proteomics, and an arrayed transposon screen, we identified that synthesis and uptake of the siderophore enterobactin is required to allow for growth in low zinc conditions. Iron-specific chelators did not replicate this phenotype and addition of supplemental iron through heme in growth media could not complement severe growth defects of enterobactin mutant K. pneumoniae experiencing zinc limitation. Finally, zinc starvation induced enterobactin production independent of the canonical zinc uptake regulator (Zur) transcription factor suggesting an unidentified regulatory mechanism by which Gram-negative pathogens may respond to zinc stress. Together, these studies expand the role of enterobactin beyond iron regulation and highlight a previously unreported link between iron and zinc homeostasis in Klebsiella pneumoniae.

microbiology↗

bioRxiv2026

A microbiota-derived protease links phage susceptibility to host epithelial responses

Bacteriophages are major ecological drivers of gut microbial ecology, yet whether bacterial mechanisms that determine phage susceptibility have consequences for the mammalian host remains poorly understood. Here, we identify dipeptidyl peptidase 11 (Dpp11a), the predominant active serine protease of the prevalent gut commensal Phocaeicola vulgatus, as an unexpected bacterial defence factor. Dpp11a protects against environmental proteases and confers resistance to bacteriophage infection. Metatranscriptomic analyses further reveal increased expression of both dpp11a and P. vulgatus-associated phage transcripts in ulcerative colitis stool samples, indicating that both components of this interaction are transcriptionally active in disease-associated human microbiomes. Using the microfluidic gut-on-a-chip co-culture model HuMiX, we show that the absence of Dpp11 is accompanied by altered epithelial tight-junction remodelling during phage-bacterial infection. Together, our findings reveal that the consequences of bacterial phage defence can extend beyond phage-bacterium interactions to the mammalian epithelium.

microbiology↗