Mycobacterium tuberculosis, the agent of human tuberculosis has developed different virulence mechanisms and virulence-associated tools during its evolution to survive and multiply inside the host. Based on previous reports and by analogy with other bacteria, phospholipases C (PLC) of M. tuberculosis were thought to be among these tools. To get deeper insights into the function of PLCs, we investigated their putative involvement in the intracellular lifestyle of M. tuberculosis, with emphasis on phagosomal rupture and virulence, thereby re-visiting a research theme of longstanding interest. Through the construction and use of an M. tuberculosis H37Rv PLC-null mutant (ΔPLC) and control strains, we found that PLCs of M. tuberculosis were not required for induction of phagosomal rupture and only showed marginal, if any, impact on virulence of M. tuberculosis in the cellular and mouse infection models used in this study. In contrast, we found that PLC-encoding genes were strongly upregulated under phosphate starvation and that PLC-proficient M. tuberculosis strains survived better than ΔPLC mutants under conditions where phosphatidylcholine served as sole phosphate source, opening new perspectives for studies on the role of PLCs in the lifecycle of M. tuberculosis.
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http://dx.doi.org/10.1038/srep16918 | DOI Listing |
( ) is the world's most deadly infectious pathogen and new drugs are urgently required to combat the emergence of multi-(MDR) and extensively-(XDR) drug resistant strains. The bacterium specifically upregulates sterol uptake pathways in infected macrophages and the metabolism of host-derived cholesterol is essential for long-term survival Here, we report the development of antitubercular small molecules that inhibit the cholesterol oxidases CYP125 and CYP142, which catalyze the initial step of cholesterol metabolism. An efficient biophysical fragment screen was used to characterize the structure-activity relationships of CYP125 and CYP142, and identify a non-azole small molecule that can bind to the heme cofactor of both enzymes.
View Article and Find Full Text PDFTuberculosis (TB) is historically the world's deadliest infectious disease. New TB drugs that can avoid pre-existing resistance are desperately needed. The β-lactams are the oldest and most widely used class of antibiotics to treat bacterial infections but, for a variety of reasons, they were largely ignored until recently as a potential treatment option for TB.
View Article and Find Full Text PDFThe recalcitrance of to antibiotic treatment has been broadly attributed to the impermeability of the organism's outer mycomembrane. However, the studies that support this inference have been indirect and/or reliant on bulk population measurements. We previously developed the P eptidoglycan A ccessibility C lick- M ediated A ssessme N t (PAC-MAN) method to covalently trap azide-modified small molecules in the peptidoglycan cell wall of live mycobacteria, after they have traversed the mycomembrane.
View Article and Find Full Text PDFOccup Ther Int
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Occupational Therapy Department, University of the Western Cape, Cape Town, South Africa.
Individuals diagnosed with tuberculosis (TB) and multidrug-resistant (MDR) TB may struggle to return to work after they have completed a rehabilitation program. Multidrug-resistant tuberculosis (MDRTB) has been seen as a condition that is resistant to treatment, hence causing individuals to be economically in-active for considerable periods of time. The aim of the current study was to explore the views of individuals living with MDRTB, individuals with TB, and health professionals treating individuals with TB and MDRTB about the development of a vocational rehabilitation program.
View Article and Find Full Text PDFKorean J Neurotrauma
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Department of Neurosurgery, College of Medicine, Korea University Guro Hospital, Seoul, Korea.
Tuberculous (TB) spondylitis, also known as Pott's disease, was first described by Percivall Pott in 1779. The diagnosis of TB spondylitis is often delayed because of the non-specific nature of the infection, which can lead to severe consequences. Differential diagnosis is especially critical in cancer patients undergoing chemotherapy who present with lymph node or bone metastasis.
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