Mutations in the GTP-binding and synergy loop domains of Mycobacterium tuberculosis ftsZ compromise its function in vitro and in vivo

Rajagopalan, Malini; Atkinson, Mark A.; Hava, Lofton; Chauhan, Ashwini; Madiraju, Murty V. V. S.

doi:10.1016/j.bbrc.2005.03.239

Cited by 30 publications

(33 citation statements)

References 34 publications

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“…M. smegmatis expressing wild-type FtsZ TB is viable, while strains expressing either of the above-mentioned mutations as the only source of FtsZ TB are nonviable (328). This is in contrast to findings for E. coli that strains with corresponding mutations in FtsZ were viable (33,247,295,394).…”

Section: How Does Ftsz Polymerize and Why Is Mycobacterial Ftsz So Scontrasting

confidence: 60%

“…This is in contrast to findings for E. coli that strains with corresponding mutations in FtsZ were viable (33,247,295,394). The findings for E. coli were interpreted to mean that wild-type levels of GTP binding and hydrolysis were not required for viability in E. coli (247,295,328,394). Using the same logic for mycobacteria, the slow polymerization and GTP hydrolysis of wild-type FtsZ TB in vitro may VOL.…”

Section: How Does Ftsz Polymerize and Why Is Mycobacterial Ftsz So Smentioning

confidence: 77%

“…Furthermore, polymers of FtsZ TB were found to be very stable (445). Two FtsZ TB point mutants have been generated and tested in vitro and in vivo (328). A mutant affected in GTP binding was found to be defective for GTP hydrolysis in vitro and polymerization both in vitro and in vivo.…”

Section: How Does Ftsz Polymerize and Why Is Mycobacterial Ftsz So Smentioning

confidence: 99%

“…A mutant affected in GTP binding was found to be defective for GTP hydrolysis in vitro and polymerization both in vitro and in vivo. A mutant with the GTPase activity abolished was found to have normal GTP binding and diminished polymerization in vitro yet could associate with the Z ring in vivo (328).…”

Section: How Does Ftsz Polymerize and Why Is Mycobacterial Ftsz So Smentioning

confidence: 99%

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Bacterial Growth and Cell Division: a Mycobacterial Perspective

Hett

Rubín

2008

Microbiol Mol Biol Rev

334

293

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SUMMARY The genus Mycobacterium is best known for its two major pathogenic species, M. tuberculosis and M. leprae, the causative agents of two of the world's oldest diseases, tuberculosis and leprosy, respectively. M. tuberculosis kills approximately two million people each year and is thought to latently infect one-third of the world's population. One of the most remarkable features of the nonsporulating M. tuberculosis is its ability to remain dormant within an individual for decades before reactivating into active tuberculosis. Thus, control of cell division is a critical part of the disease. The mycobacterial cell wall has unique characteristics and is impermeable to a number of compounds, a feature in part responsible for inherent resistance to numerous drugs. The complexity of the cell wall represents a challenge to the organism, requiring specialized mechanisms to allow cell division to occur. Besides these mycobacterial specializations, all bacteria face some common challenges when they divide. First, they must maintain their normal architecture during and after cell division. In the case of mycobacteria, that means synthesizing the many layers of complex cell wall and maintaining their rod shape. Second, they need to coordinate synthesis and breakdown of cell wall components to maintain integrity throughout division. Finally, they need to regulate cell division in response to environmental stimuli. Here we discuss these challenges and the mechanisms that mycobacteria employ to meet them. Because these organisms are difficult to study, in many cases we extrapolate from information known for gram-negative bacteria or more closely related GC-rich gram-positive organisms.

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Section: How Does Ftsz Polymerize and Why Is Mycobacterial Ftsz So Scontrasting

confidence: 60%

Section: How Does Ftsz Polymerize and Why Is Mycobacterial Ftsz So Smentioning

confidence: 77%

Section: How Does Ftsz Polymerize and Why Is Mycobacterial Ftsz So Smentioning

confidence: 99%

Section: How Does Ftsz Polymerize and Why Is Mycobacterial Ftsz So Smentioning

confidence: 99%

See 2 more Smart Citations

Bacterial Growth and Cell Division: a Mycobacterial Perspective

Hett

Rubín

2008

Microbiol Mol Biol Rev

334

293

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“…Because of the toxicity associated with elevated expression levels of ftsZ in M. tuberculosis, attempts to visualize FtsZ structures in M. tuberculosis have not been successful. At the biochemical level, FtsZ TB has been purified, characterized, and found to exhibit slow polymerization and weak GTPase activities in vitro (30,43).…”

mentioning

confidence: 99%

Mycobacterium tuberculosis Cells Growing in Macrophages Are Filamentous and Deficient in FtsZ Rings

et al. 2006

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FtsZ, a bacterial homolog of tubulin, forms a structural element called the FtsZ ring (Z ring) at the predivisional midcell site and sets up a scaffold for the assembly of other cell division proteins. The genetic aspects of FtsZ-catalyzed cell division and its assembly dynamics in Mycobacterium tuberculosis are unknown. Here, with an M. tuberculosis strain containing FtsZ TB tagged with green fluorescent protein as the sole source of FtsZ, we examined FtsZ structures under various growth conditions. We found that midcell Z rings are present in approximately 11% of actively growing cells, suggesting that the low frequency of Z rings is reflective of their slow growth rate. Next, we showed that SRI-3072, a reported FtsZ TB inhibitor, disrupted Z-ring assembly and inhibited cell division and growth of M. tuberculosis. We also showed that M. tuberculosis cells grown in macrophages are filamentous and that only a small fraction had midcell Z rings. The majority of filamentous cells contained nonring, spiral-like FtsZ structures along their entire length. The levels of FtsZ in bacteria grown in macrophages or in broth were comparable, suggesting that Z-ring formation at midcell sites was compromised during intracellular growth. Our results suggest that the intraphagosomal milieu alters the expression of M. tuberculosis genes affecting Z-ring formation and thereby cell division.Mycobacterium tuberculosis, the causative agent of tuberculosis, is an important infectious agent that globally causes more than three million new infections each year (8). Recent years have seen an increase in the number of M. tuberculosis strains that are resistant to one or more antituberculosis drugs, and this has highlighted the need for the development of a new generation of antimicrobial agents. One hallmark of the M. tuberculosis life cycle is that it exists in two metabolically distinct growth states: an active replicative state and a nonproliferative persistent state where the bacterium survives without any increase in the bacterial burden on the host. Physiological studies carried out by Wayne and colleagues indicate that M. tuberculosis cells in the hypoxiainduced nonreplicative persistent state are blocked at the cell division stage after completing DNA replication and undergo a round of cell division prior to initiation of a new round of DNA replication (40,41). This latter process is also referred to as reactivation. Development of antimycobacterial agents targeting the cell division process could potentially prevent the multiplication and subsequent proliferation of the pathogen in active, as well as reactivation, growth states.FtsZ, a bacterial homolog of tubulin, is a key player in cell division and is essential for initiation of this process (22, 32). FtsZ protein catalyzes the formation of distinct structures, referred to as FtsZ rings (Z rings), at the midcell site and sets up a scaffold for ordered assembly of other cell division proteins. The combined action of multiple cell division proteins results in septation (22,32)....

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