MtrA modulates Mycobacterium tuberculosis cell division in host microenvironments to mediate intrinsic resistance and drug tolerance

• DOI: 10.1016/j.celrep.2023.112875
• Publication Date: 2023-08-04T16:40:51Z
• Authors: Eliza J.R. Peterson; Aaron N. Brooks; David J. Reiss; Amardeep Kaur; Julie Do; Min Pan; Wei-Ju Wu; Robert Morrison; Vivek Srinivas; Warren Carter; Mario L. Arrieta-...; Rene A. Ruiz; Apoorva Bhatt; Nitin S. Baliga
• Keywords: QH301-705.5; CP: Microbiology; systems biology; Mycobacterium tuberculosis; Drug Tolerance; Article; 3. Good health; drug discovery; tuberculosis; Bacterial Proteins; transcriptional regulation; Biology (General); gene regulatory networks; Cell Division; Transcription Factors

The success of Mycobacterium tuberculosis (Mtb) is largely attributed to its ability physiologically adapt and withstand diverse localized stresses within host microenvironments. Here, we present a data-driven model (EGRIN 2.0) that captures the dynamic interplay environmental cues genome-encoded regulatory programs in Mtb. Analysis EGRIN 2.0 shows how modulation MtrAB two-component signaling system tunes Mtb growth response related microenvironmental cues. Disruption by tunable CRISPR interference confirms regulates multiple peptidoglycan hydrolases, among other targets, are important for cell division. Further, MtrA decreases effectiveness antibiotics mechanisms both intrinsic resistance drug tolerance. Together, model-enabled dissection complex regulation highlights importance as target illustrates facilitates discovery mechanistic characterization adaptation specific microenvironments host.