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

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

Automated summary

The success of Mtb is attributed to its ability to adapt and withstand stresses in host microenvironments. The EGRIN 2.0 model reveals the dynamic interaction between environmental cues and regulatory programs in Mtb. Analysis of EGRIN 2.0 shows that modulation of the MtrAB signaling system regulates Mtb growth in response to host microenvironmental cues and affects cell division. Furthermore, MtrA decreases antibiotic effectiveness through intrinsic resistance and drug tolerance mechanisms. This study highlights the importance of MtrA as a drug target and demonstrates how EGRIN 2.0 facilitates the discovery and characterization of Mtb adaptation to specific microenvironments within the host.