An unconventional regimen comprising biofilm disruptor as an adjunct with antibiotics to treat mycobacterium abscessus chronic lung disease

The National Institute of Allergy and Infectious Diseases (NIAID) awarded The Johns Hopkins University a Project Grant of $155,227 under the Allergy and Infectious Diseases Research program (CFDA 93.855) effective June 9, 2025, with completion scheduled for May 31, 2027. The grant supports proof-of-concept research on an unconventional treatment regimen for Mycobacterium abscessus (MAB) chronic lung disease, a rapidly progressive non-tuberculous mycobacterial infection currently lacking FDA-approved treatments. The research investigates the use of CMTX-101, a monoclonal antibody biofilm disruptor, administered as an adjunct to antibiotics to improve treatment efficacy by disrupting protective MAB biofilms in lung tissue that limit antibiotic penetration and effectiveness.

This research addresses critical clinical needs in treating MAB lung disease, where current standard treatment regimens demonstrate limited efficacy (30-50% cure rates), require prolonged administration periods of several months, and involve substantial drug toxicities and logistical complications associated with extended intravenous antibiotic therapy. By generating proof-of-concept data supporting biofilm disruption as a prerequisite for effective antibiotic delivery and MAB elimination, this project aims to develop a more effective treatment strategy for a patient population with limited therapeutic options and significant risk of progressive respiratory decline.

Abstract

Mycobacterium abscessus (MAB) is a rapidly growing non-tuberculous mycobacterium that can cause chronic lung disease that is associated with rapid lung function decline and is often incurable. There are no FDA- approved treatments for this indication. Patients report to the clinic with chronic disease and reduced lung function, and for the majority of them, the optimistic objective is to effectively manage the condition to prevent its deterioration, given that current treatments are largely ineffective in achieving a stable cure. In the course of chronic disease, MAB develops biofilms in the lungs, creating a protective shield against antibiotics. Existing treatments are based on repurposing of antibiotics approved for other diseases. Challenges of the currently recommended standard treatment of MAB lung disease include a) poor efficacy, b) need for treatment durations lasting several months, c) frequent drug toxicities, d) need for parenteral (IV) antibiotics, and e) complicated logistics of long-term outpatient IV antibiotic treatment. The cure rate using current treatment recommendations is estimated at 30-50%. One reason commonly cited for the limited effectiveness of antibiotics against MAB disease, as well as the need for prolonged treatment durations, is their challenge in efficiently penetrating and eliminating the MAB subpopulation present in biofilms. The overall aim of this proposal is to generate proof-of-concept data on a non-traditional strategy that acknowledges the necessity of disrupting MAB biofilms. For antibiotics to demonstrate the anti-MAB activity observed in in vitro settings, where antibiotics effectively kill planktonically growing MAB, IT might be essential to first destroy MAB biofilms in the lungs. Cmtx-101 is a monoclonal antibody that works to disrupt MAB biofilms by removing dnabii proteins, which are crucial for the lattice organization and stability of DNA providing structural integrity to MAB biofilms. Given its effective disruption of MAB biofilms in vitro, we aim to investigate in a mouse model of chronic MAB infection whether cmtx-101 can similarly disrupt MAB biofilms in the lungs. If cmtx-101 can effectively modify MAB biofilms in the lungs, the results from the proposed studies can serve as proof-of-concept for an unconventional approach to treating not only MAB disease but also other conditions where bacterial biofilms pose a challenge to effective treatment.