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Functional Analysis of Mycobacterium abscessus Electron Transport Enzymes in Host-Relevant Conditions

Award Number: F31AI203071
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/20/2026
PERIOD OF PERFORMANCE END DATE: 08/19/2029

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Functional Analysis of Mycobacterium abscessus Electron Transport Enzymes in Host-Relevant Conditions - Project Summary Mycobacterium abscessus is an opportunistic pathogen that is notoriously drug-resistant, causing severe infections with poor treatment outcomes in persons with cystic fibrosis (CF). Oxidative phosphorylation (OxPhos) is a major and highly flexible metabolic pathway that has shown promise as a drug target in multi-drug-resistant infections with the related pathogen Mycobacterium tuberculosis. However, the M. abscessus OxPhos pathway remains largely unexplored. My objective with this proposal is to determine the respiratory enzymes that support M. abscessus survival in the host environment. We hypothesize that M. abscessus responds to the CF lung environment by increasing the activity of specific OxPhos enzymes, and increased activity of these enzymes contributes to pathogenesis. My approach will draw from the expertise of my co-sponsors Dr. Miriam Braunstein and Dr. Dean Crick in molecular biology and biochemistry to investigate key enzymes for M. abscessus respiratory metabolism under host-relevant conditions. Aim I will define M. abscessus primary dehydrogenase activity during growth on synthetic CF sputum media. The primary dehydrogenases are the entry point into OxPhos, facilitating the transfer of electrons from various substrates into the electron transfer system (ETS). We will compare activity and contribution to oxygen consumption of the M. abscessus membrane-bound proline, NADH, succinate, and malate primary dehydrogenases on synthetic CF sputum media (SCFM2) versus standard mycobacterial media (7H9) using enzyme kinetics and high resolution respirometry. The intracellular levels of the electron-donating substrates (proline, NADH, succinate, malate), the electron acceptor (menaquinone), and ATP will also be quantified. This Aim will identify the primary dehydrogenases and substrates that are relied on most heavily for growth in conditions mimicking the CF lung environment. Aim II will determine the significance of PruA/B for M. abscessus in host-relevant conditions. The proline oxidation pathway – composed of Δ(1)- pyrroline-5-carboxylic dehydrogenase (PruA) and proline dehydrogenase (PruB) – is of specific interest to us because it is reported to be upregulated in M. abscessus on SCFM2, in M. tuberculosis within macrophages, and in Mycobacterium smegmatis under hypoxic/carbon-starvation conditions. Data generated in our lab also indicate PruA/B are likely important for the compensatory response when ETS functionality is impaired. To investigate the functional importance of PruA/B in M. abscessus, we will generate a ∆pruAB mutant and assess growth, respiration, and ATP production on SCFM2. We will also explore the role of PruA/B in intracellular survival by quantifying growth of the ∆pruAB mutant in macrophage infection models. Finally, we will examine PruA/B as a compensatory mechanism for impaired ETS functionality by measuring pruAB expression (qRT-PCR) +/- OxPhos inhibitors and survival of the ∆pruAB mutant when exposed to the same inhibitors. This Aim will establish the importance of PruA/B for M. abscessus growth and survival in conditions representative of the host environment. Overall, this work will address the crucial need for fundamental research in M. abscessus OxPhos.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $43,423 )
2026	2026	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	001	1	8/20/2026	NEW	$0
2026	2026	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	000	1	8/20/2026	NEW	$43,423
														Subtotal = $43,423

Grand Total All Awards = $43,423

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Functional Analysis of Mycobacterium abscessus Electron Transport Enzymes in Host-Relevant Conditions

Award Number: F31AI203071

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/20/2026

PERIOD OF PERFORMANCE END DATE: 08/19/2029

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