Friday, April 4, 2025
4/4/2025
Shorter and more effective oral regimens for M. abscessus pulmonary disease - ABSTRACT Mycobacterium abscessus (Mab) accounts for most pulmonary infections caused by fast-growing non- tuberculous mycobacteria (NTM). Incidence and prevalence rates are increasing throughout the developed world. There is currently no reliable cure for Mab pulmonary disease (Mab-PD) despite long multidrug treatments that include parenteral and poorly tolerated antibiotics. Among the factors driving the refractory nature of Mab- PD is intrinsic resistance of the pathogen to many drug classes. Here we propose complementary approaches to discover all-oral sterilizing drug regimens, either entirely made of FDA-approved agents for consideration as salvage therapy and clinical trials or integrating novel preclinical and clinical candidates for progression through the development pipeline. To shorten treatment duration in Mab-PD patients who often present with compromised immune defenses, we build novel regimens around a backbone of bactericidal agents that can rapidly reduce bacterial burden to overcome the limited contribution of the immune system. Bacteriostatic agents with established clinical utility or promising clinical trial results will be screened and included if they preserve the bactericidal activity of the backbone. First, we will propose optimized regimens with the greatest potential for sterilization according to (i) their collective ability to reach and clear bacterial populations at the site of disease and (ii) efficacy in a mouse model of Mab infection (Aim 1). To enable a more mechanistic approach to regimen development, we will characterize the cascades of drug-induced damage and system collapses leading to Mab cell death, using physiological readouts established in other bacterial species. Physiologic signatures of lethality could help design drug combinations that include bacteriostatic agents yet potentiate the bactericidal activity of partner drugs (Aim 2). To identify the determinants of intrinsic and acquired resistance to key drug classes, we will combine conventional mutant selection with genome wide CRISPR interference screens. The two approaches overcome each other’s limitations, as illustrated by the preliminary identification of specific D,D- and L,D transpeptidases as targets of a carbapenem in Mab, and a putative novel β-lactamase as a determinant of intrinsic resistance, through a CRISPRi screen. Chemical-genetic interactions will also reveal novel targets of synergy for the discovery of optimized drug combinations. Importantly, we expect that CRISPRi screens will uncover mechanisms of intrinsic resistance to guide future medicinal chemistry campaigns, as we have successfully accomplished with rifamycins overcoming ADP-ribosylation in Mab. We have assembled a multidisciplinary team of experts in microbiology and pharmacology, molecular genetics and genomics and mouse models of Mab infection. Together, we will develop enabling tools and concepts to propose novel but safe therapeutic countermeasures that can be readily tested in patients or form the basis for preclinical and clinical development.
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