---
title: "Simple sequence repeat INDELs in Mycobacterium tuberculosis influence antibiotic susceptibility"
id: "biorxiv-4-variation-in-multiple-classes-of-simple-sequence-repeats-can-alter-drug"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-4-variation-in-multiple-classes-of-simple-sequence-repeats-can-alter-drug"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.16.752248v1?rss=1"
published_at: "2026-09-20T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Simple sequence repeat INDELs in Mycobacterium tuberculosis influence antibiotic susceptibility
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-4-variation-in-multiple-classes-of-simple-sequence-repeats-can-alter-drug
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.16.752248v1?rss=1)
- **Published At:** 2026-09-20T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study analyzes variation in **simple sequence repeats (SSRs)** across clinical Mycobacterium tuberculosis (Mtb) isolates and tests their functional impact on drug susceptibility. - SSR insertions and deletions (INDELs) — including homopolymer tracts (HTs) and more complex repeat classes such as trinucleotide (triplet) SSRs — are common and under diversifying selection in global Mtb populations. - Phylogenomic comparison of clinical strains from Vietnam and Peru identified multiple variable SSRs that correlate with clinical antibiotic resistance phenotypes. - Observed variable SSR loci included frameshifting HT INDELs in ppe13, glpK, Rv2081c, and ppsA, and in-frame triplet SSR INDELs in ponA1, ppe53, and ppe59. - The authors reconstructed selected SSR INDELs in an isogenic Mtb background to test direct effects on drug potency; four variants reduced drug susceptibility in vitro. - A clinically prevalent triplet deletion (CGCdel) in **ppe53** shortened a polyalanine stretch adjacent to the conserved WxG domain, impaired processing and secretion of full-length Ppe53 protein, and conferred intermediate resistance to **isoniazid**, **rifampicin**, and **streptomycin**. - The work demonstrates that not only frameshifting HT INDELs but also subtle in-frame triplet SSR changes can modulate protein structure/function and contribute to the evolution of **antibiotic resistance**. - The study provides experimental validation linking SSR variation to altered drug potency and supports the notion of selective pressures shaping SSR diversity in Mtb. - Details on exact frequencies, statistical metrics, and full experimental protocols were reported in the source article; specific numeric results and methods were not exhaustively detailed in the summary provided here.
## Clinical Analysis & Structured Key Points
Variation in multiple classes of simple sequence repeats can alter drug susceptibility in Mycobacterium tuberculosis | bioRxiv Skip to main content New Results Variation in multiple classes of simple sequence repeats can alter drug susceptibility in Mycobacterium tuberculosis View ORCID Profile Peter O. Oluoch , Michael J Luna , Gavin Fujimori , Mayashree Das , Roger Vargas Jr. , Kadamba G Papavinasasundaram , View ORCID Profile Maha R. Farhat , Christopher M. Sassetti doi: https://doi.org/10.64898/2026.09.16.752248 Peter O. Oluoch 1 University of Massachusetts Medical School Department of Physiology: University of Massachusetts Chan Medical School Department of Microbiology and Physiological Systems; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Peter O. Oluoch Michael J Luna 1 University of Massachusetts Medical School Department of Physiology: University of Massachusetts Chan Medical School Department of Microbiology and Physiological Systems; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Gavin Fujimori 2 University of Massachusetts Medical School Department of Molecular Genetics and Microbiology: University of Massachusetts Chan Medical School Department of Microbiology and Physiological Systems; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mayashree Das 1 University of Massachusetts Medical School Department of Physiology: University of Massachusetts Chan Medical School Department of Microbiology and Physiological Systems; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Roger Vargas Jr. 3 Harvard Medical School; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kadamba G Papavinasasundaram 2 University of Massachusetts Medical School Department of Molecular Genetics and Microbiology: University of Massachusetts Chan Medical School Department of Microbiology and Physiological Systems; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Maha R. Farhat 3 Harvard Medical School; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Maha R. Farhat Christopher M. Sassetti 4 University of Massachusetts Medical School Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: christopher.sassetti{at}umassmed.edu Abstract Info/History Metrics Preview PDF Abstract Insertions and deletions (INDELs) in simple sequence repeats (SSRs) generate relatively high-frequency reversible genetic changes that facilitate bacterial adaptation to changing environments. Analyses of global Mycobacterium tuberculosis (Mtb) isolates indicate that many SSRs are under diversifying selection, and several of the resulting INDELs in homopolymer tracts (HTs) can increase the pathogen's fitness during exposure to host and antibiotic stresses. However, the functional impact of most variable SSRs, particularly those within more complex repeat sequences than HT, remains unclear. Here, we combine phylogenomic analysis of clinical Mtb strains from Vietnam and Peru with in vitro experimental validation of engineered strains to identify SSR INDELs that alter antibiotic susceptibility. Our findings demonstrate that INDELs across multiple SSRs of differing repeat composition are highly variable and correlate with clinical antibiotic resistance. These variants included frameshifting HT INDELs in ppe13, glpK, Rv2081c, and ppsA, and in-frame trinucleotide (triplet) SSR INDELS in ponA1, ppe53, and ppe59 that produce much more subtle changes in protein structure. Reconstruction of these INDELs in an isogenic background identified four variants that directly reduce drug potency, including a triplet SSR deletion in ppe53 that conferred intermediate resistance to isoniazid, rifampicin, and streptomycin. The clinically prevalent ppe53 CGCdel mutation shortens a polyalanine stretch adjacent to the conserved WxG domain and impairs the processing and secretion of the full-length protein. Overall, our work provides additional evidence of selective pressure across Mtb SSRs and demonstrates the significance of in-frame INDELs within triplet SSRs, highlighting their contribution to the evolution of antibiotic resistance. Competing Interest Statement The authors have declared no competing interest. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted September 20, 2026. Download PDF Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Variation in multiple classes of simple sequence repeats can alter drug susceptibility in Mycobacterium tuberculosis Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Variation in multiple classes of simple sequence repeats can alter drug susceptibility in Mycobacterium tuberculosis Peter O. Oluoch , Michael J Luna , Gavin Fujimori , Mayashree Das , Roger Vargas Jr. , Kadamba G Papavinasasundaram , Maha R. Farhat , Christopher M. Sassetti bioRxiv 2026.09.16.752248; doi: https://doi.org/10.64898/2026.09.16.752248 Share This Article: Copy Citation Tools Variation in multiple classes of simple sequence repeats can alter drug susceptibility in Mycobacterium tuberculosis Peter O. Oluoch , Michael J Luna , Gavin Fujimori , Mayashree Das , Roger Vargas Jr. , Kadamba G Papavinasasundaram , Maha R. Farhat , Christopher M. Sassetti bioRxiv 2026.09.16.752248; doi: https://doi.org/10.64898/2026.09.16.752248 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Areas All Articles Animal Behavior and Cognition (8013) Biochemistry (18739) Bioengineering (14888) Bioinformatics (44418) Biophysics (22599) Cancer Biology (19723) Cell Biology (26899) Clinical Trials (138) Developmental Biology (13965) Ecology (21005) Epidemiology (2067) Evolutionary Biology (25455) Genetics (16166) Genomics (23507) Immunology (18705) Microbiology (42503) Molecular Biology (18059) Neuroscience (93451) Paleontology (700) Pathology (2977) Pharmacology and Toxicology (5095) Physiology (8114) Plant Biology (15999) Scientific Communication and Education (2095) Synthetic Biology (4560) Systems Biology (10235) Zoology (2391)
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