# New drugs for non-tuberculous mycobacterial (NTM) lung disease in patients with cystic fibrosis

> **NIH NIH U19** · HACKENSACK UNIVERSITY MEDICAL CENTER · 2021 · $722,728

## Abstract

Abstract
Whereas tuberculosis (TB) incidence is decreasing, disease due to relatives of Mycobacterium tuberculosis, a
group of intrinsically resistant bacteria called ‘Non-tuberculous (non-TB) Mycobacteria’ or NTM, is increasing.
These emerging NTM pathogens specifically threaten vulnerable groups, including cystic fibrosis patients and
aging populations. Treatment of NTM disease can require years of chemotherapy with multiple antibiotics to
achieve cure, if cure is achieved. The most problematic NTM pathogen is Mycobacterium abscessus (Mab). Mab
lung disease is considered not curable and death rates can exceed 50%. It was thought that Mab infections are
acquired exclusively from environmental sources. However, recently it was demonstrated that Mab became
transmittable from human to human. There is an urgent medical need for new antibiotics that work against this
‘super-bug’. De novo - i.e. new chemical entities / new target - drug discovery takes 10 years or more to bring
new medicines to patients. An alternative approach to new antibiotics is ‘repositioning’ of exiting drugs. Several
antibiotics show some activity against NTM, however, issues such as low potency and toxicity limit or preclude
their clinical use. We refer to ‘repositioning’ as the pathogen-specific chemical optimization of antibiotic classes
that act against pharmacologically validated targets, but have been developed for infectious diseases other than
NTM. Since these drug classes include members that are FDA-approved, attrition rates are lower and the
probability of success is higher than incurred through de novo drug discovery. For instance, the oxazolidinone
linezolid (target ribosome) shows some anti-Mab activity but suffers from low potency and toxicity. In screens of
oxazolidinone libraries and follow-up characterization work with Merck we have identified lead compounds with
improved potency and reduced toxicity, thus validating the strategy. Similarly, the rifamycin rifampicin (target
RNA polymerase) shows poor activity against Mab. We identified rifamycin lead compounds exhibiting improved
potency. Here, we will subject our two leads to optimization campaigns to deliver preclinical development
candidates with tolerability, exposure and efficacy in established and novel mouse models of Mab lung disease.
NTM infection models do exist, however, they largely rely on immune-deficient mouse strains and a systemic
infection approach, whereas natural transmission occurs by inhalation. Importantly, current models show limited
similarities in pathology to human NTM lung disease. Robust, more predictive mouse models are needed.
Standard mouse strains are mostly resistant against Mab infections and clear the bacterium. In preliminary work
we tested a small set of clinical Mab isolates against different wild type mouse strains and could show that some
combinations deliver improved bacterial growth and pathology. In parallel to our two lead optimization projects
(aim 1 and 2), we wil...

## Key facts

- **NIH application ID:** 10138983
- **Project number:** 5U19AI142731-03
- **Recipient organization:** HACKENSACK UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Thomas Dick
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $722,728
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10138983

## Citation

> US National Institutes of Health, RePORTER application 10138983, New drugs for non-tuberculous mycobacterial (NTM) lung disease in patients with cystic fibrosis (5U19AI142731-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10138983. Licensed CC0.

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