The PDIM paradox of Mycobacterium tuberculosis : new solutions to a persistent problem.

Autor: Mulholland CV; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA., Wiggins TJ; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA., Cui J; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA., Vilchèze C; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA., Rajagopalan S; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA., Shultis MW; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA., Reyes-Fernández EZ; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA., Jacobs WR Jr; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA., Berney M; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2023 Oct 16. Date of Electronic Publication: 2023 Oct 16.
DOI: 10.1101/2023.10.16.562559
Abstrakt: Phthiocerol dimycocerosate (PDIM) is an essential virulence lipid of Mycobacterium tuberculosis . In vitro culturing rapidly selects for spontaneous mutations that cause PDIM loss leading to virulence attenuation and increased cell wall permeability. We discovered that PDIM loss is due to a metabolic deficiency of methylmalonyl-CoA that impedes the growth of PDIM-producing bacilli. This can be remedied by supplementation with odd-chain fatty acids, cholesterol, or vitamin B 12 . We developed a much-needed facile and scalable routine assay for PDIM production and show that propionate supplementation enhances the growth of PDIM-producing bacilli and selects against PDIM-negative mutants, analogous to in vivo conditions. Our results solve a major issue in tuberculosis research and exemplify how discrepancies between the host and in vitro nutrient environments can attenuate bacterial pathogenicity.
Competing Interests: Competing interests C.V.M. and M.B. are inventors on a pending patent related to this work (US Patent Application No. 63/527,831, filed 20 July 2023). The authors declare that they have no other competing interests.
Databáze: MEDLINE
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