# Investigating the role of prophage encoded gene products on mycobacterial gene expression and intrinsic antibiotic resistance

> **NIH NIH R15** · UNIVERSITY OF MAINE ORONO · 2022 · $432,274

## Abstract

PROJECT SUMMARY
The goal of the proposed research is to understand how prophages regulate mycobacterial
antibiotic resistance and alter gene expression in mycobacteria. Drug-resistant infections caused
by clinically important mycobacteria continue to be a significant public health burden.
Mycobacterium abscessus is an emerging pathogen in cystic fibrosis patients with a treatment
success rate of only 45%, and is considered one of the most drug-resistant mycobacteria.
Resistant isolates commonly display increased expression of intrinsic antibiotic resistance genes,
making drug treatment challenging. M. abscessus isolates are typically lysogens, meaning their
genomes carry one or more prophages, integrated viral genomes, that have the potential to
regulate intrinsic antibiotic resistance. The mechanism by which prophage alter gene expression
and antibiotic resistance in mycobacteria is not yet understood and is the focus of this grant.
Expression of the transcriptional regulator whiB7 increases in response to stresses, such as sub-
inhibitory concentrations of antibiotics and the intracellular environment of macrophages and
plays a critical role in mycobacterial intrinsic antibiotic resistance and survival in macrophages
(8). Our lab showed for the first time that prophage contribute to intrinsic antibiotic
resistance and increased expression of whiB7, which in turn positively regulates a large
set of intrinsic antibiotic resistance genes (8-10). We identified a novel group of prophages
found in the genomes of M. abscessus and M. chelonae that belong to cluster MabR (7, 11) and
determined that the MabR prophage, McProf, increases M. chelonae resistance to
aminoglycosides, cornerstone antibiotic treatments for M. abscessus/chelonae infections (9). We
found that mycobacteria carrying McProf have an enhanced whiB7 response particularly when
superinfected by a second phage. It is not understood how the prophage McProf interacts with
the second prophage to drive changes in whiB7 expression and intrinsic resistance. We
hypothesize that genes expressed from the McProf genome detect stress and regulate
antibiotic resistance in mycobacteria through the induction of whiB7. To understand the
mechanisms of whiB7 regulation in mycobacterial lysogens, we propose characterizing the
cellular stresses that enhance the whiB7 response in bacterial lysogens carrying the McProf
prophage and identify and characterize McProf genes that upregulate whiB7 in response to
stress.

## Key facts

- **NIH application ID:** 10579008
- **Project number:** 1R15GM148943-01
- **Recipient organization:** UNIVERSITY OF MAINE ORONO
- **Principal Investigator:** Sally Molloy
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $432,274
- **Award type:** 1
- **Project period:** 2022-09-20 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10579008

## Citation

> US National Institutes of Health, RePORTER application 10579008, Investigating the role of prophage encoded gene products on mycobacterial gene expression and intrinsic antibiotic resistance (1R15GM148943-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10579008. Licensed CC0.

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