Cell Surface Remodeling of Mycobacterium abscessus under Cystic Fibrosis Airway Growth Conditions.

Understanding the physiological processes underlying the ability of Mycobacterium abscessus to become a chronic pathogen of the cystic fibrosis (CF) lung is important to the development of prophylactic and therapeutic strategies to better control and treat pulmonary infections caused by these bacteria. Gene expression profiling of a diversity of M. abscessus complex isolates points to amino acids being significant sources of carbon and energy for M. abscessus in both CF sputum and synthetic CF medium and to the bacterium undergoing an important metabolic reprogramming in order to adapt to this particular nutritional environment. Cell envelope analyses conducted on the same representative isolates further revealed unexpected structural alterations in major cell surface glycolipids known as the glycopeptidolipids (GPLs). Besides showing an increase in triglycosylated forms of these lipids, CF sputum- and synthetic CF medium-grown isolates presented as yet unknown forms of GPLs representing as much as 10% to 20% of the total GPL content of the cells, in which the classical amino alcohol located at the carboxy terminal of the peptide, alaninol, is replaced with the branched-chain amino alcohol leucinol. Importantly, both these lipid changes were exacerbated by the presence of mucin in the culture medium. Collectively, our results reveal potential new drug targets against M. abscessus in the CF airway and point to mucin as an important host signal modulating the cell surface composition of this pathogen

Comparative physiology of Mycobacterium abscessus in synthetic laboratory medium and cystic fibrosis sputum

2019 Fall.Includes bibliographical references.Mycobacterium abscessus complex is a group of rapid-growing nontuberculous mycobacteria that are multidrug resistant and that cause chronic pulmonary infections in individuals with cystic fibrosis (CF) and other pre-disposing conditions. Research progress is challenged by the lack of laboratory models that mimic the lung environment, a nutritionally complex environment not well represented by current laboratory medium. In this study, the growth characteristics and gene expression profile of a diverse panel of M. abscessus isolates were characterized and compared when grown in 7H9 Middlebrook medium (a synthetic Mycobacterium laboratory culture medium); Synthetic Cystic Fibrosis Medium 2 (SCFM2), a medium which mimics the composition of CF sputum; and actual patient CF sputum. Tests were also performed measuring the antibiotic susceptibility and characterizing the cell envelope composition of the M. abscessus isolates in these media. Although the medium composition did not affect the antibiotic susceptibility or growth of the isolates, it caused changes in fatty acid and outer membrane lipid compositions which may account, at least in part, for observed differences in the subsequent infectivity of the isolates inside macrophages and epithelial cells. The gene expression profiles showed similar upregulation of pathways related to carbon metabolism for Mycobacterium abscessus grown in SCFM2 and grown in CF sputum while reaffirming the complexity of CF sputum and the many metabolic and structural adaptations that M. abscessus undergoes during growth in varied environments

2-Aminoimidazoles Inhibit <i>Mycobacterium abscessus</i> Biofilms in a Zinc-Dependent Manner

Biofilm growth is thought to be a significant obstacle to the successful treatment of Mycobacterium abscessus infections. A search for agents capable of inhibiting M. abscessus biofilms led to our interest in 2-aminoimidazoles and related scaffolds, which have proven to display antibiofilm properties against a number of Gram-negative and Gram-positive bacteria, including Mycobacterium tuberculosis and Mycobacterium smegmatis. The screening of a library of 30 compounds led to the identification of a compound, AB-2-29, which inhibits the formation of M. abscessus biofilms with an IC50 (the concentration required to inhibit 50% of biofilm formation) in the range of 12.5 to 25 μM. Interestingly, AB-2-29 appears to chelate zinc, and its antibiofilm activity is potentiated by the addition of zinc to the culture medium. Preliminary mechanistic studies indicate that AB-2-29 acts through a distinct mechanism from those reported to date for 2-aminoimidazole compounds