Isoprenoid biosynthesis in bacterial pathogens

Heuston, Sinéad; Begley, Máire; Gahan, Cormac G. M.; Hill, Colin

doi:10.1099/mic.0.051599-0

Cited by 142 publications

(124 citation statements)

References 97 publications

Supporting

Mentioning

120

Contrasting

Order By: Relevance

“…1A). The peptidoglycan biosynthetic metabolite 1-deoxy-xylulose-5-phosphate (DXP), which is required for the synthesis of isoprenoid (30), was also less abundant in the mutant strains (Fig. 1B).…”

Section: Resultsmentioning

confidence: 99%

Stringent Response Factors PPX1 and PPK2 Play an Important Role in Mycobacterium tuberculosis Metabolism, Biofilm Formation, and Sensitivity to Isoniazid In Vivo

Chuang

Dutta

Hung

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

g Mycobacterium tuberculosis remains a global health threat largely due to the lengthy duration of curative antibiotic treatment, contributing to medical nonadherence and the emergence of drug resistance. This prolonged therapy is likely due to the presence of M. tuberculosis persisters, which exhibit antibiotic tolerance. Inorganic polyphosphate [poly(P)] is a key regulatory molecule in the M. tuberculosis stringent response mediating antibiotic tolerance. The polyphosphate kinase PPK1 is responsible for poly(P) synthesis in M. tuberculosis, while the exopolyphosphatases PPX1 and PPX2 and the GTP synthase PPK2 are responsible for poly(P) hydrolysis. In the present study, we show by liquid chromatography-tandem mass spectrometry that poly(P)-accumulating M. tuberculosis mutant strains deficient in ppx1 or ppk2 had significantly lower intracellular levels of glycerol-3-phosphate (G3P) and 1-deoxy-xylulose-5-phosphate. Real-time PCR revealed decreased expression of genes in the G3P synthesis pathway in each mutant. The ppx1-deficient mutant also showed a significant accumulation of metabolites in the tricarboxylic acid cycle, as well as altered arginine and NADH metabolism. Each poly(P)-accumulating strain showed defective biofilm formation, while deficiency of ppk2 was associated with increased sensitivity to plumbagin and meropenem and deficiency of ppx1 led to enhanced susceptibility to clofazimine. A DNA vaccine expressing ppx1 and ppk2, together with two other members of the M. tuberculosis stringent response, M. tuberculosis rel and sigE, did not show protective activity against aerosol challenge with M. tuberculosis, but vaccine-induced immunity enhanced the killing activity of isoniazid in a murine model of chronic tuberculosis. In summary, poly(P)-regulating factors of the M. tuberculosis stringent response play an important role in M. tuberculosis metabolism, biofilm formation, and antibiotic sensitivity in vivo.

show abstract

Section: Resultsmentioning

confidence: 99%

Stringent Response Factors PPX1 and PPK2 Play an Important Role in Mycobacterium tuberculosis Metabolism, Biofilm Formation, and Sensitivity to Isoniazid In Vivo

Chuang

Dutta

Hung

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…1 This pathway is present in most bacteria as well as in the protozoan parasite, Plasmodium falciparum , the causative agent of the most common and serious form of malaria. 2,3 This pathway is not used by humans and is essential for survival and is, therefore, an important drug target. In addition, the MEP pathway is present in plants, making inhibitors of interest as potential herbicides.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the 4Fe–4S proteins IspG and IspH: an EPR, ENDOR and HYSCORE investigation

Guerra

Wang

et al. 2014

Chem. Sci.

View full text Add to dashboard Cite

IspG and IspH are proteins that are involved in isoprenoid biosynthesis in most bacteria as well as in malaria parasites and are important drug targets. They contain cubane-type 4Fe-4S clusters that are involved in unusual 2H+/2e− reductions. Here, we report the results of electron paramagnetic resonance spectroscopic investigations of the binding of amino- and thiolo-HMBPP (HMBPP=E-1-hydroxy-2-methyl-but-2-enyl 4-diphosphate) IspH substrate-analog inhibitors to both proteins, as well as the binding of HMBPP and an acetylene diphosphate inhibitor, to IspG. The results show that amino-HMBPP binds to reduced IspH by Fe-C π-bonding with the olefinic carbons interacting with the unique 4th Fe in the 4Fe-4S cluster, quite different to the direct Fe-N ligation seen with the oxidized protein. No such π-complex is observed when amino-HMBPP binds to reduced IspG. No EPR signal is observed with IspH in the presence of dithionite and thiolo-HMBPP, suggesting that the 4Fe-4S cluster is not reduced, consistent with the presence of a 420 nm feature in the absorption spectrum (characteristic of an oxidized cluster). However, with IspG, the EPR spectrum in the presence of dithionite and thiolo-HMBPP is very similar to that seen with HMBPP. The binding of HMBPP to IspG was studied using hyperfine sublevel correlation spectroscopy with 17O and 13C labeled samples: the results rule out direct Fe-O bonding and indicate π-bonding. Finally, the binding to IspG of a potent acetylene diphosphate inhibitor was studied by using electron-nuclear double resonance spectroscopy with 13C labeled ligands: the large hyperfine couplings indicate strong Fe-C π-bonding with the acetylenic group. These results illustrate a remarkable diversity in binding behavior for HMBPP-analog inhibitors, opening up new routes to inhibitor design of interest in the context of anti-bacterial and anti-malarial drug discovery, as well as “cubane-type” metallo-biochemistry, in general.

show abstract

“…Of note, an isomer of this metabolite, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), is a precursor of the nonmevalonate pathway of isoprenoid biosynthesis in the majority of human pathogens (43 ). This metabolite is the most potent stimulant of human V␥2V␦2 T cells, thereby triggering immune response.…”

Section: Tions Of Deoxyhexose (5 ) and 36-anhydrogalactose (3 )mentioning

confidence: 99%

Untargeted Metabolic Profiling Identifies Altered Serum Metabolites of Type 2 Diabetes Mellitus in a Prospective, Nested Case Control Study

Drogan¹,

et al. 2015

View full text Add to dashboard Cite

show abstract

Isoprenoid biosynthesis in bacterial pathogens

Cited by 142 publications

References 97 publications

Stringent Response Factors PPX1 and PPK2 Play an Important Role in Mycobacterium tuberculosis Metabolism, Biofilm Formation, and Sensitivity to Isoniazid In Vivo

Stringent Response Factors PPX1 and PPK2 Play an Important Role in Mycobacterium tuberculosis Metabolism, Biofilm Formation, and Sensitivity to Isoniazid In Vivo

Inhibition of the 4Fe–4S proteins IspG and IspH: an EPR, ENDOR and HYSCORE investigation

Untargeted Metabolic Profiling Identifies Altered Serum Metabolites of Type 2 Diabetes Mellitus in a Prospective, Nested Case Control Study

Contact Info

Product

Resources

About