Mycobacterium: Genomics and Molecular Biology

Publisher: Caister Academic Press
Editors: Tanya Parish and Amanda Brown
ISBN: 978-1-904455-40-0
"a select collection of reviews of mycobacterial 'hot topics' written by leaders in the respective fields. Each chapter is a thorough treatment of the topic, summarizing current understanding and highlighting gaps in knowledge. ... an excellent introduction to the topics covered and will be valuable for all mycobacteriologists." review from Microbiology Today

Further reading: Mycobacterium: Genomics and Molecular Biology

Labels: book review, mycobacteria, mycobacteriologist, mycobacterium

Sulphur is an essential component of all living cells. The importance of sulphur is well-represented by the sulfhydryl (thiol) functional group, lying at the center of many chemical reactions in biology. Thiol-based reactions have diverse biological functions: thiols in thioredoxins provide reductive power for the synthesis of biological molecules; thiols in coenzyme A facilitate the oxidation of pyruvate and fatty acids to generate energy for living cells; and thiols in glutathione and mycothiol are involved in detoxifying hazardous molecules, as well as maintaining the redox balance of living cells. Additionally, sulphur-containing molecules function as messengers in intracellular and intra-species communation. Sulphur is also a constituent of many other biomolecules like cysteine, methionine, biotin, lipoic acid, molybdopterin, thionucleosides in tRNAs, and thiamine.

Sulphur metabolic pathways of pathogenic bacteria, such as mycobacteria, hold importance both for its biological implications as well as discovering drug targets against enzymes in these pathways. Several enzymes in the sulphur metabolic pathways are essential for mycobacterial survival. The endeavour to map the sulphur metabolic pathways has been greatly facilitated by the emerging information drawn from mycobacterial genome sequencing. Sulphur metabolism plays a role in the pathogenesis of the human pathogen, Mycobacterium tuberculosis, contributing to intracellular survival and virulence. The other mycobacterial species include: Mycobacterium leprae which causes leprosy in humans, Mycobacterium bovis which causes tuberculosis in cattle, Mycobacterium avium which causes disease in immune-compromised individuals, M. bovis Bacille Calmette-Guérin (BCG) which is an attenuated strain of M. bovis used as a vaccine strain and Mycobacterium smegmatis which is a saprophytic non-pathogenic species used extensively as a laboratory model for mycobacterial research.

One-third of the world's population is infected with latent tuberculosis, indicating that the human immune system is capable of controlling the M. tuberculosis infection but not always able to eradicate the bacterium. It has been suggested that sulphur metabolism may have a the role in the prevention of eradication of M. tuberculosis by the human immune system.

from Chapter 7 "Sulphur Metabolism in Mycobacteria" (Ryan H. Senaratne and Kathleen Y. Dunphy) in Mycobacterium: Genomics and Molecular Biology

Further reading: Mycobacterium: Genomics and Molecular Biology

Labels: mycobacteria, mycobacterium, sulphur, tuberculosis

Mycobacterium tuberculosis, also known as as the "tubercle bacillus" is the bacterium that causes most cases of tuberculosis. The genome has been sequenced and recent research on the genomics and molecular biology of mycobacteria has contributed greatly to our knowledge of this pathogen. Some of the most important recent findings are highlighted here.

Strain Variation and Evolution in Mycobacteria
Mycobacterium tuberculosis appears to be more genetically diverse than generally assumed. There is mounting evidence that this genetic diversity translates into significant phenotypic differences between clinical isolates. M. tuberculosis exhibits a biogeographic population structure and different strain lineages are associated with different geographic regions. Phenotypic studies in the laboratory and in clinical settings suggest that this macro-evolutionary strain variation has implications for the development of new diagnostics and vaccines. Micro-evolutionary variation affects the relative fitness and transmission dynamics of antibiotic-resistant strains. In the light of the emerging epidemic of multidrug-resistant and extensively drug-resistant tuberculosis, there is an urgent need to improve our understanding of the evolution and ecological consequences of strain variation in drug-resistant M. tuberculosis. Further reading: Mycobacterium: Genomics and Molecular Biology

Hypervirulent Mycobacterium tuberculosis
Tuberculosis outbreaks are often caused by hypervirulent strains of Mycobacterium tuberculosis. In experimental animal infections, these clinical isolates elicit unusual immunopathology and may be either hyper- or hypoinflammatory. Similarly, recombinant hypervirulent M. tuberculosis mutants, which exhibit increased bacterial burden or decreased host survival times in model infections, induce a spectrum of inflammatory responses. The majority of hypervirulent mutants identified have deletions in cell wall modifying enzymes or regulators that respond to environmental stimuli. Studies of these mutants have provided insight into the mechanisms that enable M. tuberculosis to mask its full pathogenic potential, inducing a granuloma that provides a protective niche and enables the bacilli to sustain a long-term persistent infection. Further reading: Mycobacterium: Genomics and Molecular Biology

Electron Transport and Respiration in Mycobacteria
Bacteria have evolved a modular respiratory system that enables them to optimize energy production in environments that are variable and may be hostile. By adjusting the composition of the system to suit the specific conditions encountered, the organism is able to thrive in a particular environment. The flexibility conferred by a modular respiratory system is critical to the survival of many bacterial pathogens, including Mycobacterium tuberculosis. The composition of the respiratory systems of sequenced mycobacterial species can be deduced from a comparative analysis of their respiratory gene complements and from the function of specific system components. Common themes have emerged from studies of various models of growth and persistence and can be related to the physiology of this pathogen during infection. Exciting new developments in tuberculosis drug discovery are predicated on targeting respiration and electron transport through inhibition of type II NADH dehydrogenase, ATP synthase, and menaquinone biosynthetic enzymes. Further reading: Mycobacterium: Genomics and Molecular Biology

Lipid biosynthetic machinery of Mycobacterium tuberculosis
Mycobacterium tuberculosis posseses a repertoire of complex lipids. Many of these lipids are crucial to its survival and virulence. Fatty-acyl components of the mycobacterial lipids are synthesised by the concerted action of fatty acid synthases (FASs) and polyketide synthases (PKSs). While the single multifunctional type I FAS carries out de novo biosynthesis from acetyl-CoA, the multicomponent type II FAS generates the very long acyl chains from type I FAS products. Polyketide synthases take over from FAS to complete the biosynthesis of the unusual acyl chains of many exotic lipids like mycolic acids, phthioceroldimycocerosate ester, sulfolipids and mannosyl-beta-1-phophomycoketides. The novel family of fatty acyl-adenylate ligases (FAALs) is crucial to this intricate enzymatic network. FAALs mediate the crosstalk between FAS and PKS by activating long-chain fatty acids to fatty acyl-adenylates which are transacylated onto the PKSs. Further reading: Mycobacterium: Genomics and Molecular Biology

DNA Repair in Mycobacteria
Sequence comparisons indicate that mycobacteria possess the majority of the key DNA repair pathways identified in other bacterial species, including base excision repair, nucleotide excision repair, recombination repair and non-homologous end-joining. However, there are some notable differences such as the absence of a mismatch repair system, as well as variations in the components of other repair pathways. Currently functional studies of DNA repair within mycobacterial species are limited, but this is an expanding area of research. It has been demonstrated that DNA-damage induced mutagenesis is mediated by a different class of DNA polymerase to that used in Escherichia coli. Although the classical SOS system of gene regulation in response to DNA damage is conserved and functional in mycobacteria, many of the DNA repair genes whose expression increases following DNA damage are controlled by an alternative system or systems that are yet to be characterised. The increase in expression observed for a number of Mycobacterium tuberculosis DNA repair genes in infection models suggests that DNA repair might be particularly important during pathogenesis. Further reading: Mycobacterium: Genomics and Molecular Biology

Oxygen, Nitric Oxide, and Carbon Monoxide Signaling in Mycobacteria
Mycobacterium tuberculosis is an aerobe that can survive extended periods of anaerobiosis. The bacillus responds to inhibition of respiration during hypoxic conditions as well as exposure to NO and CO by the induction of over 60 genes, referred to as the "dormancy regulon". Control of the dormancy regulon by NO and CO, not just hypoxia, is mediated by a three component regulatory system composed of two sensors, DosT and DosS and a transcriptional regulator DosR. The dormancy proteins are part of a programmed strategy employed by the bacilli to survive in the absence of aerobic respiration. Further reading: Mycobacterium: Genomics and Molecular Biology

Sulphur Metabolism in Mycobacteria
Sulphur is a key life-supporting element. The recent combined efforts of genomic analysis and laboratory studies have greatly clarified the mycobacterial sulphur metabolic pathways. Sulphur metabolism contributes to intracellular survival and virulence of Mycobacterium tuberculosis. Several enzymes in the sulphur metabolic pathways are essential for mycobacterial survival. Further reading: Mycobacterium: Genomics and Molecular Biology

The Eukaryotic-like Serine/Threonine Protein Kinase Family in Mycobacteria
Mycobacteria have a complex life style comprising different environments and developmental stages. Signal sensing and transduction leading to cellular responses must be tightly regulated to allow survival under variable conditions. Prokaryotes normally regulate their signal transduction processes through two-component systems, however, the genome sequence of Mycobacterium tuberculosis revealed a large number of eukaryotic-like serine/threonine kinases. It is becoming clear that in M. tuberculosis, many of these kinases are involved in the regulation of metabolic processes, transport of metabolites, cell division and virulence. Further reading: Mycobacterium: Genomics and Molecular Biology

Protein Secretion Systems of Mycobacteria
Mycobacteria have a highly complex cell wall. Specialised secretion systems are therefore required to transport proteins across this cell wall. However, genome analysis shows that, apart from the omnipresent Sec and Tat systems, all of the known secretion pathways of other bacteria are absent. Mycobacteria do have a second SecA protein (SecA2) that is involved in the extracellular accumulation of a specific protein subset. In addition, a new secretion pathway was recently identified that is responsible for the secretion of various proteins into the culture supernatant. This pathway is present in multiple copies in the mycobacteria and has been named the type VII secretion pathway. Further reading: Mycobacterium: Genomics and Molecular Biology

Labels: bacillus, bacteriology, bacterium, mycobacteria, mycobacterium, tuberculosis