ChemInform Abstract: The Mycobacterial Cell-Wall as Target for Antimycobacterial Drugs. Part 1. Synthesis and Activity of Some Diphenylalkyl Analogues of Mycolic Acids.

ChemInform ◽  
1988 ◽  
Vol 19 (20) ◽  
Author(s):  
D. C. LEYSEN ◽  
A. HAEMERS ◽  
L. BLANCHAERT ◽  
I. VAN ASSCHE ◽  
W. BOLLAERT ◽  
...  
Keyword(s):  
Cell Wall ◽  
Mycolic Acids ◽  
Mycobacterial Cell ◽  
Mycobacterial Cell Wall

scholarly journals MmpL3 is a lipid transporter that binds trehalose monomycolate and phosphatidylethanolamine

2019 ◽  
Vol 116 (23) ◽  
pp. 11241-11246 ◽  
Author(s):  
Chih-Chia Su ◽  
Philip A. Klenotic ◽  
Jani Reddy Bolla ◽  
Georgiana E. Purdy ◽  
Carol V. Robinson ◽  
...  
Keyword(s):  
Cell Wall ◽  
Cell Envelope ◽  
Native Mass Spectrometry ◽  
Mycolic Acids ◽  
Mycobacterial Cell ◽  
Exact Function ◽  
Species Specific ◽  
Mycobacterial Cell Wall ◽  
Trehalose Monomycolate ◽  
Lipid Transporter

The cell envelope ofMycobacterium tuberculosisis notable for the abundance of mycolic acids (MAs), essential to mycobacterial viability, and of other species-specific lipids. The mycobacterial cell envelope is extremely hydrophobic, which contributes to virulence and antibiotic resistance. However, exactly how fatty acids and lipidic elements are transported across the cell envelope for cell-wall biosynthesis is unclear. Mycobacterial membrane protein Large 3 (MmpL3) is essential and required for transport of trehalose monomycolates (TMMs), precursors of MA-containing trehalose dimycolates (TDM) and mycolyl arabinogalactan peptidoglycan, but the exact function of MmpL3 remains elusive. Here, we report a crystal structure ofMycobacterium smegmatisMmpL3 at a resolution of 2.59 Å, revealing a monomeric molecule that is structurally distinct from all known bacterial membrane proteins. A previously unknown MmpL3 ligand, phosphatidylethanolamine (PE), was discovered inside this transporter. We also show, via native mass spectrometry, that MmpL3 specifically binds both TMM and PE, but not TDM, in the micromolar range. These observations provide insight into the function of MmpL3 and suggest a possible role for this protein in shuttling a variety of lipids to strengthen the mycobacterial cell wall.

scholarly journals Synthesis of a Di-Mycoloyl Tri-Arabinofuranosyl Glycerol Fragment of the Mycobacterial Cell Wall, Based on Synthetic Mycolic Acids

Molecules ◽  
2019 ◽  
Vol 24 (19) ◽  
pp. 3596
Author(s):  
Ali ◽  
Mohammed ◽  
Dulayymi ◽  
Baird
Keyword(s):  
Cell Wall ◽  
Cell Walls ◽  
Stereoselective Synthesis ◽  
Complex Mixtures ◽  
Mycolic Acids ◽  
Mycobacterial Cell ◽  
Antigenic Properties ◽  
Mycobacterial Cell Wall ◽  
Structural Classes

Fragments of mycobacterial cell walls such as arabinoglycerol mycolate and dimycoloyl diarabinoglycerol, comprising complex mixtures of mycolic acids, have immunostimulatory and antigenic properties. A related di-mycoloyl tri-arabinofuranosyl glycerol fragment has been isolated from cell wall hydrolysates. An effective stereoselective synthesis of tri-arabinofuranosyl glycerol, followed by coupling with stereochemically defined mycolic acids of different structural classes, to provide unique di-mycoloyl tri-arabinofuranosyl glycerols is now described.

scholarly journals Mycobacteriophage Ms6 LysB specifically targets the outer membrane of Mycobacterium smegmatis

Microbiology ◽  
2010 ◽  
Vol 156 (5) ◽  
pp. 1497-1504 ◽  
Author(s):  
Filipa Gil ◽  
Anna E. Grzegorzewicz ◽  
Maria João Catalão ◽  
João Vital ◽  
Michael R. McNeil ◽  
...  
Keyword(s):  
Cell Wall ◽  
Outer Membrane ◽  
Mycobacterium Smegmatis ◽  
Mycolic Acid ◽  
Head Group ◽  
Lipolytic Enzyme ◽  
Ester Bond ◽  
Mycolic Acids ◽  
Mycobacterial Cell ◽  
Mycobacterial Cell Wall

LysB, a mycobacteriophage Ms6-encoded protein, was previously identified as a lipolytic enzyme able to hydrolyse the ester bond in lipase and esterase substrates. In the present work, we show that LysB can hydrolyse lipids containing mycolic acids from the outer membrane of the mycobacterial cell wall. LysB was shown to hydrolyse the mycolic acids from the mycolyl-arabinogalactan–peptidoglycan complex where the mycolates of the inner leaflet of the outer membrane are covalently attached to an arabinosyl head group. In addition, treatment of the extractable lipids from Mycobacterium smegmatis, Mycobacterium bovis BCG and Mycobacterium tuberculosis H37Ra with LysB showed that trehalose 6,6′-dimycolate (TDM), a trehalose diester of two mycolic acid molecules, was hydrolysed by the enzyme. We have also determined the structures of the mycolic acid molecules that form the M. smegmatis TDM. The identification of a phage-encoded enzyme that targets the outer membrane of the mycobacterial cell wall enhances our understanding of the mechanism of mycobacteriophage lysis.

scholarly journals MmpL3 is a lipid transporter that binds trehalose monomycolate and phosphatidylethanolamine

2019 ◽  
Author(s):  
Chih-Chia Su ◽  
Philip Klenotic ◽  
Jani Reddy Bolla ◽  
Georgiana Purdy ◽  
Carol Robinson ◽  
...  
Keyword(s):  
Cell Wall ◽  
Cell Envelope ◽  
Native Mass Spectrometry ◽  
Mycolic Acids ◽  
Mycobacterial Cell ◽  
Exact Function ◽  
Species Specific ◽  
Mycobacterial Cell Wall ◽  
Trehalose Monomycolate ◽  
Lipid Transporter

The cell envelope of Mycobacterium tuberculosis is notable for the abundance of mycolic acids (MAs), which are essential to mycobacterial viability, and other species-specific lipids. The mycobacterial cell envelope is extremely hydrophobic, contributes to virulence and antibiotic resistance. Yet, exactly how fatty acids and lipidic elements are transported across the cell envelope for cell wall biosynthesis is unclear. Mycobacterial membrane protein Large 3 (MmpL3) is essential and required for transport of trehalose monomycolates (TMMs), precursors of MA containing trehalose dimycolates (TDM) and mycolyl arabinogalactan peptidoglycan (mAGP), but the exact function of MmpL3 remains elusive. Here, we report a high-resolution crystal structure of M. smegmatis MmpL3, revealing a monomeric molecule that is structurally distinct from all known bacterial membrane proteins. A previously unknown MmpL3 ligand, phosphatidylethanolamine (PE), was discovered inside this transporter. We also show, via native mass spectrometry, that MmpL3 specifically binds both TMM and PE, but not TDM, in the micromolar range. These observations provide insight into the function of MmpL3 and suggest a possible role for this protein in shuttling a variety of lipids to strengthen the mycobacterial cell wall.

Conserved Molecular Superlattices in a Series of Homologous Synthetic Mycobacterial Cell-Wall Lipids Forming Interdigitated Bilayers

Langmuir ◽  
2016 ◽  
Vol 32 (48) ◽  
pp. 12693-12701 ◽  
Author(s):  
Birte Martin-Bertelsen ◽  
Anan Yaghmur ◽  
Henrik Franzyk ◽  
Sarah Justesen ◽  
Jacob J. K. Kirkensgaard ◽  
...  
Keyword(s):  
Cell Wall ◽  
Mycobacterial Cell ◽  
Mycobacterial Cell Wall

scholarly journals Mycobacterial cell wall biosynthesis: a multifaceted antibiotic target

Parasitology ◽  
2016 ◽  
Vol 145 (2) ◽  
pp. 116-133 ◽  
Author(s):  
KATHERINE A. ABRAHAMS ◽  
GURDYAL S. BESRA
Keyword(s):  
Cell Wall ◽  
Drug Targets ◽  
Complex Structure ◽  
Supporting Cell ◽  
Chemotherapeutic Agents ◽  
World Health ◽  
Mycobacterial Cell ◽  
Clinical Drugs ◽  
Health Organization ◽  
Mycobacterial Cell Wall

SUMMARYMycobacterium tuberculosis(Mtb), the etiological agent of tuberculosis (TB), is recognized as a global health emergency as promoted by the World Health Organization. Over 1 million deathsperyear, along with the emergence of multi- and extensively-drug resistant strains ofMtb, have triggered intensive research into the pathogenicity and biochemistry of this microorganism, guiding the development of anti-TB chemotherapeutic agents. The essential mycobacterial cell wall, sharing some common features with all bacteria, represents an apparent ‘Achilles heel’ that has been targeted by TB chemotherapy since the advent of TB treatment. This complex structure composed of three distinct layers, peptidoglycan, arabinogalactan and mycolic acids, is vital in supporting cell growth, virulence and providing a barrier to antibiotics. The fundamental nature of cell wall synthesis and assembly has rendered the mycobacterial cell wall as the most widely exploited target of anti-TB drugs. This review provides an overview of the biosynthesis of the prominent cell wall components, highlighting the inhibitory mechanisms of existing clinical drugs and illustrating the potential of other unexploited enzymes as future drug targets.

scholarly journals Organization of the mycobacterial cell wall: a nanoscale view

2007 ◽  
Vol 456 (1) ◽  
pp. 117-125 ◽  
Author(s):  
David Alsteens ◽  
Claire Verbelen ◽  
Etienne Dague ◽  
Dominique Raze ◽  
Alain R. Baulard ◽  
...  
Keyword(s):  
Cell Wall ◽  
Mycobacterial Cell ◽  
Mycobacterial Cell Wall
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