{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:04:12Z","timestamp":1790208252117,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,20]]},"group-title":"Microbiology","reference-count":82,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  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\n                  <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                  (\n                  <jats:italic>Mtb<\/jats:italic>\n                  ) isolates indicate that many SSRs are under diversifying selection, and several of the resulting INDELs in homopolymer tracts (HTs) can increase the pathogen\u2019s 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\n                  <jats:italic>Mtb<\/jats:italic>\n                  strains from Vietnam and Peru with\n                  <jats:italic>in vitro<\/jats:italic>\n                  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\n                  <jats:italic>ppe13<\/jats:italic>\n                  ,\n                  <jats:italic>glpK<\/jats:italic>\n                  ,\n                  <jats:italic>Rv2081c,<\/jats:italic>\n                  and\n                  <jats:italic>ppsA<\/jats:italic>\n                  , and in-frame trinucleotide (triplet) SSR INDELS in\n                  <jats:italic>ponA1, ppe53,<\/jats:italic>\n                  and\n                  <jats:italic>ppe59<\/jats:italic>\n                  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\n                  <jats:italic>ppe53<\/jats:italic>\n                  that conferred intermediate resistance to isoniazid, rifampicin, and streptomycin. The clinically prevalent\n                  <jats:italic>\n                    ppe53 CGC\n                    <jats:sub>del<\/jats:sub>\n                  <\/jats:italic>\n                  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\n                  <jats:italic>Mtb<\/jats:italic>\n                  SSRs and demonstrates the significance of in-frame INDELs within triplet SSRs, highlighting their contribution to the evolution of antibiotic resistance.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Author Summary<\/jats:title>\n                  <jats:p>\n                    Large scale analyses of genome sequences from clinical isolates of\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    have associated many mutations with altered antibiotic susceptibility, informing sequence-based prediction of treatment efficacy. However, previous studies often focus on single nucleotide polymorphisms, limiting our understanding of the roles of more complex mutagenic processes in the adaptation to drug pressure. In particular, insertions and deletions (INDELs) in repetitive regions are quite common, but their impact is incompletely understood. We show that INDELs in simple sequence repeats (SSRs), particularly in-frame INDELs within triplet SSRs, are not only associated with clinical resistance but also confer intermediate antibiotic resistance. In particular, a common one-codon deletion in the\n                    <jats:italic>ppe53 gene<\/jats:italic>\n                    shortens a polyalanine stretch in the encoded protein and appears to disrupt critical interactions with the secretion machine, thereby impairing processing and localization of the full-length protein. Our findings reveal a previously unappreciated mechanism of\n                    <jats:italic>Mtb<\/jats:italic>\n                    adaptation to antibiotic stress driven by in-frame mutations in triplet SSRs.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.16.752248","type":"posted-content","created":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T18:00:19Z","timestamp":1789927219000},"source":"Crossref","is-referenced-by-count":0,"title":["Variation in multiple classes of simple sequence repeats can alter drug susceptibility in\n                  <i>Mycobacterium tuberculosis<\/i>"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7451-4993","authenticated-orcid":false,"given":"Peter O.","family":"Oluoch","sequence":"first","affiliation":[{"name":"Department of Microbiology, University of Massachusetts Medical School, Worcester, Massachusetts, 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Luna","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Massachusetts Medical School, Worcester, Massachusetts, 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin","family":"Fujimori","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Massachusetts Medical School, Worcester, Massachusetts, 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayashree","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Massachusetts Medical School, Worcester, Massachusetts, 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Roger","family":"Vargas","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, 25 Shattuck St., Boston, MA, 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kadamba G.","family":"Papavinasasundaram","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Massachusetts Medical School, Worcester, Massachusetts, 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3871-5760","authenticated-orcid":false,"given":"Maha R.","family":"Farhat","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, 25 Shattuck St., Boston, MA, 02115, USA"},{"name":"Division of Pulmonary & Critical Care, Massachusetts General Hospital, 55 Fruit St, Boston, MA, 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Sassetti","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Massachusetts Medical School, Worcester, Massachusetts, 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026092316301130000_2026.09.16.752248v1.1","unstructured":"Global Tuberculosis Report 2025. 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