Intellectual Merit:

The CMNR bacteria (Corynebacterium, Mycobacterium, Nocardia and Rhodococcus) are soil inhabitants, plant commensals, industrial microbes and pathogens that are of great interest to pharmaceutical, environmen?tal, chemical, and energy industries. The diversity of habitats colonized by CMNR bacteria is rooted in their ability to adapt to new environments by dynamically altering the composition of complex fatty acids in their cell wall. The goal of this award was to elucidate gene regulatory networks that allow CMNR bacteria to selectively alter the composition of their cell wall in response to environmental changes. Towards this end, we identified an evolutionarily conserved gene regulatory network in mycobacteria that regulates the biosynthesis of cell wall fatty acids in response to environmental stress. Specifically, we identified the Mycolic Acid Desaturase Regulator (MadR) as a transcriptional repressor responsible for regulating the two essential fatty acid desaturases, desA1 and desA2 in mycobacteria. We showed that under anaerobic conditions there was a transient increase in expression of desA1/desA2, followed by a significant repression after 40hrs of hypoxia. We also demonstrated that increased desA1/desA2 expression resulted in cell wall fatty acid modifications (i.e. hyper-desaturated fatty acids) or decreased cell wall fatty acid production upon desA1/desA2 repression. Furthermore, we have detailed the regulatory mechanism of MadR, identifying that MadR binds to saturated acyl-CoA?s of chain length C16 and above to release binding at the promoters and drive expression of desA1/desA2. Our results implicate MadR as being a sensor for maintaining the appropriate composition and levels of cell wall fatty acids. Through acyl-CoA ligand availability, MadR plays a a dual role, both responsible for driving cell wall fatty acid modifications early upon environmental stress and for limiting fatty acid synthesis for long-term persistence. Altogether, this project successfully leveraged complementary expertise across two research groups in the US (funded by NSF) and the UK (funded by BBSRC) to address the fundamental and biotechnologically important question of how CMNR bacteria adapt to new environments through cell wall modifications.

Broader Impacts:

This award significantly expanded a suite of middle and high school curriculum modules which use an interdisciplinary systems approach to explore complex, global issues and phenomenon such as food insecurity, nutrient cycling and antimicrobial resistance. In addition to creating new instructional materials, this award also facilitated the improved use of these materials in the US and across the UK through teacher professional development. The educational activities include modeling natural food production systems and using network models to study ecosystem dynamics, functioning, and resilience. The educational activities were designed through collaborations between senior scientists, postdoctoral fellows, high school student interns, and educators. Furthermore, these materials have been disseminated through thousands of teachers and are in use with thousands of students in order to improve student learning, retention, engagement, and complex problem-solving skills.

Last Modified: 11/29/2020
Modified by: Eliza Peterson