Genetics of Peptidoglycan Biosynthesis

Pavelka, Martin S.; Mahapatra, Sebabrata; Crick, Dean C.

doi:10.1128/microbiolspec.mgm2-0034-2013

Cited by 22 publications

(25 citation statements)

References 158 publications

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“…Our metabolomics analysis revealed a decreased abundance of 1-deoxy-D-xylulose-5-phosphate in both mutants. To investigate the possibility that poly(P) accumulation leads to altered peptidoglycan biosynthesis, we used RT-PCR to evaluate the expression of relevant genes (40). The genes encoding L,D-transpeptidase, ldtA and ldtB, were downregulated in both mutant strains (41).…”

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

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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.

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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

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“…The cytoplasmic synthesis of PG precursors in Mtb is for the most part similar to that of other bacteria (for a recent review, Pavelka et al ., 2014). Consistently, most of the genes involved have been found primarily by homology.…”

Section: The Major Cell Envelope Glycoconjugates Of Mtbmentioning

confidence: 76%

“…1]. The detailed structure and biosynthesis of the PG of Mtb have been reviewed recently (Pavelka et al ., 2014). The PG of mycobacteria belongs to the A1γ chemotype as does that of Escherichia coli and a number of other bacteria.…”

Section: The Major Cell Envelope Glycoconjugates Of Mtbmentioning

confidence: 99%

“…A number of transglycosylases, transpeptidases and carboxypeptidases including eight penicillin-binding proteins (PBPs), mediate the polymerization of the sugar backbone and cross-linking of the peptides of PG in Mtb (Pavelka et al ., 2014). The role of some of these enzymes in PG biosynthesis, however, is not fully understood.…”

Section: The Major Cell Envelope Glycoconjugates Of Mtbmentioning

confidence: 99%

“…The role of some of these enzymes in PG biosynthesis, however, is not fully understood. The Mtb PBPs PbpA (Rv0016c) and PbpB (FtsI; Rv2163c) also play critical roles in cell division (Pavelka et al ., 2014). A specific family of enzymes known as L,D-transpeptidases accounts for the formation of the 3,3 crosslinks in PG.…”

Section: The Major Cell Envelope Glycoconjugates Of Mtbmentioning

confidence: 99%

See 2 more Smart Citations

The cell envelope glycoconjugates ofMycobacterium tuberculosis

Angala

Belardinelli

Huc-Claustre

et al. 2014

Critical Reviews in Biochemistry and Molecular Biology

132

191

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Tuberculosis (TB) remains the second most common cause of death due to a single infectious agent. The cell envelope of Mycobacterium tuberculosis (Mtb), the causative agent of the disease in humans, is a source of unique glycoconjugates and the most distinctive feature of the biology of this organism. It is the basis of much of Mtb pathogenesis and one of the major causes of its intrinsic resistance to chemotherapeutic agents. At the same time, the unique structures of Mtb cell envelope glycoconjugates, their antigenicity and essentiality for mycobacterial growth provide opportunities for drug, vaccine, diagnostic and biomarker development, as clearly illustrated by recent advances in all of these translational aspects. This review focuses on our current understanding of the structure and biogenesis of Mtb glycoconjugates with particular emphasis on one of most intriguing and least understood aspect of the physiology of mycobacteria: the translocation of these complex macromolecules across the different layers of the cell envelope. It further reviews the rather impressive progress made in the last ten years in the discovery and development of novel inhibitors targeting their biogenesis.

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Have we realized the full potential of β‐lactams for treating drug‐resistant TB?

Story-Roller

Lamichhane

2018

IUBMB Life

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β-lactams are the most widely used antibiotics and are effective against a spectrum of pathogenic bacteria. Here, we focus on the state-of-the-art understanding of the molecular underpinnings that determine the overall efficacy of β-lactams against TB and include historical perspectives of this antibiotic class against this ancient disease. We summarize literature that describes why earlier generations of β-lactams are ineffective and the potential promise of newer β-lactams that exhibit improved efficacy against TB. Emerging evidence warrants renewed consideration of newer β-lactams in regimens for treatment of drug-resistant TB. © 2018 IUBMB Life, 70(9):881-888, 2018.

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Genetics of Peptidoglycan Biosynthesis

Cited by 22 publications

References 158 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

The cell envelope glycoconjugates ofMycobacterium tuberculosis

Have we realized the full potential of β‐lactams for treating drug‐resistant TB?

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