Benzothiazinones mediate killing of Corynebacterineae by blocking decaprenyl phosphate recycling involved in cell wall biosynthesis.
Benzothiazinones (BTZs) are a new class of sulfur containing heterocyclic compounds that target DprE1, an oxidoreductase involved in the epimerization of decaprenyl-phosphoribose (DPR) to decaprenyl-phosphoarabinose (DPA) in the Corynebacterineae, such as Corynebacterium glutamicum and Mycobacterium tuberculosis. As a result, BTZ inhibition leads to inhibition of cell wall arabinan biosynthesis. Previous studies have demonstrated the essentiality of dprE1. In contrast, Cg-UbiA a ribosyltransferase, which catalyzes the first step of DPR biosynthesis prior to DprE1, when genetically disrupted, produced a viable mutant, suggesting that although BTZ biochemically targets DprE1, killing also occurs through chemical synthetic lethality, presumably through the lack of decaprenyl phosphate recycling. To test this hypothesis, a derivative of BTZ, BTZ043, was examined in detail against C. glutamicum and C. glutamicum::ubiA. The wild type strain was sensitive to BTZ043; however, C. glutamicum::ubiA was found to be resistant, despite possessing a functional DprE1. When the gene encoding C. glutamicum Z-decaprenyl-diphosphate synthase (NCgl2203) was overexpressed in wild type C. glutamicum, resistance to BTZ043 was further increased. This data demonstrates that in the presence of BTZ, the bacilli accumulate DPR and fail to recycle decaprenyl phosphate, which results in the depletion of decaprenyl phosphate and ultimately leads to cell death.
From the School of Biosciences, Institute of Microbiology and Infection, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom and.
Shipra
S
Grover
Luke J
LJ
Alderwick
Arun K
AK
Mishra
Karin
K
Krumbach
Jan
J
Marienhagen
Lothar
L
Eggeling
Apoorva
A
Bhatt
Gurdyal S
GS
Besra
D000429:Alcohol Oxidoreductases; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D048230:Corynebacterium glutamicum / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000378:metabolism*; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*; D013843:Thiazines / Q000737:chemistry / Q000494:pharmacology*
C540716:2-(2-methyl-1,4-dioxa-8-azaspiro(4.5)dec-8-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D011106:Polyisoprenyl Phosphates; D013141:Spiro Compounds; D013843:Thiazines; C068697:decaprenyl phosphate; D010088:Oxidoreductases; D000429:Alcohol Oxidoreductases; C583625:DprE1 protein, Mycobacterium tuberculosis
Bacterial Metabolism; Carbohydrate Metabolism; Cell Wall; Drug Resistance; Polysaccharide