Genetics of Capsular Polysaccharides and Cell Envelope (Glyco)lipids

Daffé, Mamadou; Crick, Dean C.; Jackson, Mary

doi:10.1128/microbiolspec.mgm2-0021-2013

Cited by 73 publications

(67 citation statements)

References 359 publications

(457 reference statements)

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“…The mycolic acids form a second lipid bilayer which constitutes a diffusion barrier similar to the outer membrane of Gram-negative bacteria (11) (for a recent review on the structure and assembly of the mycobacterial cell wall, see reference 12). As corynebacteria and mycobacteria have no teichoic acids within their cell walls and only mycobacteria harbor capsule-like structures (13), the function of LCP proteins in these species and their relation to cell wall biosynthesis remains unclear. A recent study revealed that the LCP protein CpsA of Mycobacterium marinum plays an important role in cell wall assembly and that it is essential for proliferation in macrophages and virulence in zebrafish (14).…”

Section: Importancementioning

confidence: 99%

Impact of LytR-CpsA-Psr Proteins on Cell Wall Biosynthesis in Corynebacterium glutamicum

et al. 2016

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Proteins of the LCP (LytR, CpsA, Psr) family have been shown to inherit important roles in bacterial cell wall biosynthesis. However, their exact function in the formation of the complex cell wall structures of the Corynebacteriales, including the prominent pathogens Mycobacterium tuberculosis and Corynebacterium diphtheriae, remains unclear. Here, we analyzed the role of the LCP proteins LcpA and LcpB of Corynebacterium glutamicum, both of which localize at regions of nascent cell wall biosynthesis. A strain lacking lcpB did not show any growth-related or morphological phenotype under the tested conditions. In contrast, conditional silencing of the essential lcpA gene resulted in severe growth defects and drastic morphological changes. Compared to the wild-type cell wall, the cell wall of this mutant contained significantly less mycolic acids and a reduced amount of arabinogalactan. In particular, rhamnose, a specific sugar component of the linker that connects arabinogalactan and peptidoglycan, was decreased. Complementation studies of the lcpA-silencing strain with several mutated and truncated LcpA variants suggested that both periplasmic domains are essential for function whereas the cytoplasmic N-terminal part is dispensable. Successful complementation experiments with proteins of M. tuberculosis and C. diphtheriae revealed a conserved function of LCP proteins in these species. Finally, pyrophosphatase activity of LcpA was shown in an in vitro assay. Taken together, our results suggest that LCP proteins are responsible for the transfer of arabinogalactan onto peptidoglycan in actinobacterial species and support a crucial function of a so-far-uncharacterized C-terminal domain (LytR_C domain) which is frequently found at the C terminus of the LCP domain in this prokaryotic phylum. IMPORTANCEAbout one-third of the world's population is infected with Mycobacterium tuberculosis, and multiple-antibiotic resistance provokes the demand for novel antibiotics. The special cell wall architecture of Corynebacteriales is critical for treatments because it is either a direct target or a barrier that the drug has to cross. Here, we present the analysis of LcpA and LcpB of the closely related Corynebacterium glutamicum, the first of which is an essential protein involved in cell wall biogenesis. Our work provides a comprehensive characterization of the impact of LCP proteins on cell wall biogenesis in this medically and biotechnologically important class of bacteria. Special focus is set on the two periplasmic LcpA domains and their contributions to physiological function.

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Section: Importancementioning

confidence: 99%

Impact of LytR-CpsA-Psr Proteins on Cell Wall Biosynthesis in Corynebacterium glutamicum

et al. 2016

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“…Studies conducted for decades to follow by generations of outstanding biochemists in France, the United Kingdom, and the United States, in particular, have resulted in a thorough understanding of the chemical structures of these lipids. Their detailed descriptions have been compiled in several recent books and reviews and the reader is referred to these for further reading on this topic (Brennan 1988;Barry et al 1998;Kaur et al 2009;Daffé et al 2014). Developments in the genetic manipulation of mycobacteria in the 1990s and the release of the first complete genome sequence of Mtb in 1998 have provided a major impetus to the study of the biosynthesis of these compounds with the result that many of the enzymes and transporters involved in their biogenesis have now been identified.…”

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confidence: 99%

The Mycobacterial Cell Envelope--Lipids

Jackson

2014

Cold Spring Harbor Perspectives in Medicine

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“…tuberculosis has an unusual cell envelope, characterized by an outer membrane (the mycomembrane) consisting largely of long-chain mycolic acids (MA) and a number of atypical lipids (7,8). Most of these lipids are important to the viability and/or virulence of the bacteria (9), which is why much effort continues to be devoted to identifying, analyzing, and targeting enzymes involved in their metabolism (9)(10)(11)(12)(13). Consequently, much is known about the pathways responsible for biosynthesis of the mycolic acids and other components of the mycomembrane (Fig.…”

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confidence: 99%

Evolution of Mycolic Acid Biosynthesis Genes and Their Regulation during Starvation in Mycobacterium tuberculosis

et al. 2015

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Mycobacterium tuberculosis, the etiological agent of tuberculosis, is a Gram-positive bacterium with a unique cell envelope composed of an essential outer membrane. Mycolic acids, which are very-long-chain (up to C 100 ) fatty acids, are the major components of this mycomembrane. The enzymatic pathways involved in the biosynthesis and transport of mycolates are fairly well documented and are the targets of the major antituberculous drugs. In contrast, only fragmented information is available on the expression and regulation of the biosynthesis genes. In this study, we report that the hadA, hadB, and hadC genes, which code for the mycolate biosynthesis dehydratase enzymes, are coexpressed with three genes that encode proteins of the translational apparatus. Consistent with the well-established control of the translation potential by nutrient availability, starvation leads to downregulation of the hadABC genes along with most of the genes required for the synthesis, modification, and transport of mycolates. The downregulation of a subset of the biosynthesis genes is partially dependent on Rel Mtb , the key enzyme of the stringent response. We also report the phylogenetic evolution scenario that has shaped the current genetic organization, characterized by the coregulation of the hadABC operon with genes of the translational apparatus and with genes required for the modification of the mycolates. IMPORTANCEMycobacterium tuberculosis infects one-third of the human population worldwide, and despite the available therapeutic arsenal, it continues to kill millions of people each year. There is therefore an urgent need to identify new targets and develop a better understanding of how the bacterium is adapting itself to host defenses during infection. A prerequisite of this understanding is knowledge of how this adaptive skill has been implanted by evolution. Nutrient scarcity is an environmental condition the bacterium has to cope with during infection. In many bacteria, adaptation to starvation relies partly on the stringent response. M. tuberculosis's unique outer membrane layer, the mycomembrane, is crucial for its viability and virulence. Despite its being the target of the major antituberculosis drugs, only scattered information exists on how the genes required for biosynthesis of the mycomembrane are expressed and regulated during starvation. This work has addressed this issue as a step toward the identification of new targets in the fight against M. tuberculosis. Mycobacterium tuberculosis, the etiological agent of tuberculosis, infects one-third of humans worldwide, with 9 million new cases and 1.5 million people dying each year from this disease (77). A long-standing challenge to the fight against tuberculosis is the ability of the pathogen to develop a nonreplicating, persistent, drug-tolerant form (1-3). In addition, the emergence of multidrug-resistant (MDR), extremely drug-resistant (XDR) (4, 5), and total-drug-resistant (TDR) strains (6) underscores the urgent need to identify new therapeutic targe...

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Genetics of Capsular Polysaccharides and Cell Envelope (Glyco)lipids

Cited by 73 publications

References 359 publications

Impact of LytR-CpsA-Psr Proteins on Cell Wall Biosynthesis in Corynebacterium glutamicum

Impact of LytR-CpsA-Psr Proteins on Cell Wall Biosynthesis in Corynebacterium glutamicum

The Mycobacterial Cell Envelope--Lipids

Evolution of Mycolic Acid Biosynthesis Genes and Their Regulation during Starvation in Mycobacterium tuberculosis

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