Biology subjects

Belardinelli, J. M.

Publications and source records attributed to Belardinelli, J. M..

2 recordsLinked to original sources

bioRxiv2022

Mechanical morphotype switching as an adaptive response in mycobacteria

Invading microbes face a myriad of cidal mechanisms of phagocytes that inflict physical damage to microbial structures. How intracellular bacterial pathogens adapt to these stresses is not fully understood. Here, we report a new virulence mechanism by which mycobacteria alter the mechanical stiffness of their cell surface to become refractory to killing during infection. Long-Term Time-Lapse Atomic Force Microscopy was used to reveal a process of "mechanical morphotype switching" in mycobacteria exposed to host intracellular stress. A "soft" mechanical morphotype switch enhances tolerance to intracellular macrophage stress, including cathelicidin. Genetic manipulation, by deletion of uvrA, or pharmacological treatment, with bedaquiline, locked mycobacteria into a "soft" mechanical morphotype state, enhancing survival in macrophages. Our study proposes microbial mechanical adaptation as a new axis for surviving host-mediated stressors. One-Sentence SummaryBacteria alter their cell surface mechanical properties to increase survival during macrophage infection.

microbiology↗

bioRxiv2019

Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification

Translational frameshift errors are often deleterious to the synthesis of functional proteins as they lead to the production of truncated or inactive proteins. TrmD (tRNA-(N(1)G37) methyltransferase) is an essential tRNA modification enzyme in bacteria that prevents +1 errors in the reading frame during protein translation and has been identified as a therapeutic target for several bacterial infections. Here we validate TrmD as a target in Mycobacterium abscessus and describe the application of a structure-guided fragment-based drug discovery approach for the design of a new class of inhibitors against this enzyme. A fragment library screening followed by structure-guided chemical elaboration of hits led to the development of compounds with potent in vitro TrmD inhibitory activity. Several of these compounds exhibit activity against planktonic M. abscessus and Mycobacterium tuberculosis. The compounds were further active in macrophage infection models against Mycobacterium leprae and M. abscessus suggesting the potential for novel broad-spectrum mycobacterial drugs.

biochemistry↗