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Mycobacterial peptidoglycan (PG), displaying characteristic modifications comprising the amidation of D-\n                    <jats:italic>iso<\/jats:italic>\n                    -glutamate (D-\n                    <jats:italic>i<\/jats:italic>\n                    Glu) and the\n                    <jats:italic>N<\/jats:italic>\n                    -glycolylation of muramic acid, is therefore a promising therapeutic target. The genes encoding the enzymes mediating these modifications (\n                    <jats:italic>murT<\/jats:italic>\n                    \/\n                    <jats:italic>gatD<\/jats:italic>\n                    and\n                    <jats:italic>namH<\/jats:italic>\n                    ) were silenced in\n                    <jats:italic>Mtb<\/jats:italic>\n                    using CRISPR interference (CRISPRi) to investigate their impact on \u03b2-lactam susceptibility and host immune responses. First, qRT-PCR confirmed successful target mRNA knockdown and phenotyping assays corroborated the essentiality of D-\n                    <jats:italic>i<\/jats:italic>\n                    Glu amidation for mycobacterial growth, in contrast to muramic acid\n                    <jats:italic>N<\/jats:italic>\n                    -glycolylation. The susceptibility assays demonstrated that both PG modifications promote \u03b2-lactam resistance. Indeed, we observed reductions in the minimum fractional inhibitory concentration index (FICI\n                    <jats:sub>min<\/jats:sub>\n                    ) value for AMX\/MEM\u2009+\u2009CLA and EMB combinations following the depletion of both PG modifications. Furthermore, D-\n                    <jats:italic>i<\/jats:italic>\n                    Glu amidation was found to promote\n                    <jats:italic>Mtb<\/jats:italic>\n                    fitness within THP-1-derived macrophages 6\u00a0days post-infection. Infection with MurT\/GatD-depleted\n                    <jats:italic>Mtb<\/jats:italic>\n                    was associated with increased IL-1\u03b2 and decreased IL-10, whereas NamH depletion was linked to increased IL-1\u03b2 and IL-10 levels. Altogether, our findings unveiled the potential of targeting these PG modifications for the development of innovative therapeutic regimens against TB.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-59172-9","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T05:05:13Z","timestamp":1782191113000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic interference of distinctive Mycobacterium tuberculosis peptidoglycan modifications enhances \u03b2-lactam susceptibility and reveals expression-sensitive host immune dynamics"],"prefix":"10.1038","volume":"16","author":[{"given":"C\u00e1tia","family":"Silveiro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Marques","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Oliven\u00e7a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Pires","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsa","family":"Anes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Jo\u00e3o","family":"Catal\u00e3o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"59172_CR1","unstructured":"World Health Organization. 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