Interdependence of bacterial cell division and genome segregation and its potential in drug development

Misra, Hari S.; Maurya, Ganesh Kumar; Chaudhary, Reema; Misra, Chitra Seetharam

doi:10.1016/j.micres.2017.12.013

Cited by 18 publications

(8 citation statements)

References 183 publications

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“…Alteration in the nucleoid morphology is reminiscent of the aberrant replication status of a cell (Misra et al, 2018). Morphological analysis by scanning electron microscopy indicates a significant increase in bacterial cell length due to DNA gyrase depletion (Figure 2C).…”

Section: Resultsmentioning

confidence: 99%

Conditional Silencing by CRISPRi Reveals the Role of DNA Gyrase in Formation of Drug-Tolerant Persister Population in Mycobacterium tuberculosis

Choudhary

Sharma

Kumar

et al. 2019

Front. Cell. Infect. Microbiol.

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Drug tolerance in mycobacterial pathogens is a global concern. Fluoroquinolone (FQ) treatment is widely used for induction of persisters in bacteria. Although FQs that target DNA gyrase are currently used as second-line anti-tuberculosis (TB) drugs, little is known about their impact on Mycobacterium tuberculosis (Mtb) persister formation. Here we explored the CRISPRi-based genetic repression for better understanding the effect of DNA gyrase depletion on Mtb physiology and response to anti-TB drugs. We find that suppression of DNA gyrase drastically affects intra- and extracellular growth of Mtb. Interestingly, gyrase depletion in Mtb leads to activation of RecA/LexA-mediated SOS response and drug tolerance via induction of persister subpopulation. Chemical inhibition of RecA in gyrase-depleted bacteria results in reversion of persister phenotype and better killing by antibiotics. This study provides evidence that inhibition of SOS response can be advantageous in improving the efficacy of anti-TB drugs and shortening the duration of current TB treatment.

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Section: Resultsmentioning

confidence: 99%

Conditional Silencing by CRISPRi Reveals the Role of DNA Gyrase in Formation of Drug-Tolerant Persister Population in Mycobacterium tuberculosis

Choudhary

Sharma

Kumar

et al. 2019

Front. Cell. Infect. Microbiol.

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“…The process of cytokinesis has been widely studied in Bacillus subtilis and Escherichia coli, as well as in S. aureus [16][17][18][19][20], Streptococcus pneumonia [21][22][23][24], and M. tuberculosis [25][26][27][28][29][30][31][32]. In these bacterial cells, the cell envelope layer is invaginated by the divisome which, in turn, forms a septum between replicated chromosomes at the middle of the cell.…”

Section: Pathway Of Bacterial Cytokinesismentioning

confidence: 99%

The key bacterial cell division protein FtsZ as a novel antibacterial drug target

Rahman¹,

Wang²,

Wang³

et al. 2020

Bosn J of Basic Med Sci

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The number of multidrug-resistant bacterial strains is currently increasing; thus, the determination of drug targets for the development of novel antimicrobial drugs is urgently needed. FtsZ, the prokaryotic homolog of the eukaryotic tubulin, is a GTP-dependent prokaryotic cytoskeletal protein that is conserved among most bacterial strains. In vitro studies revealed that FtsZ self-assembles into dynamic protofilaments or bundles, and it forms a dynamic Z-ring at the center of the cell, leading to septation and consequent cell division. The potential role of FtsZ in the blockage of cell division makes FtsZ a highly attractive target for developing novel antibiotics. Researchers have been working on synthetic molecules and natural products as inhibitors of FtsZ. Accumulating data suggest that FtsZ may provide the platform for the development of novel antibiotics. In this review, we summarize recent advances on the properties of FtsZ protein and bacterial cell division, as well as on the development of FtsZ inhibitors.

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“…Filamentous structures on DNA play a genome protective role in prokaryotes: eg DAN protein forms a rigid collaborative filament that reduces accessibility during anoxia (55), while the Vibrio cholera protein ParA2 forms protective filamentous structures on DNA during segregation (56). Structural characterization has demonstrated how these filaments function and, in the case of ParA2, can be targeted therapeutically (57). The coating of ssDNA by RPA in eukaryotes, also protect DNA from the activity of nucleases, and directs the specific activity of others (58)(59)(60).…”

Section: How Would a Locked Id2 Filament Mediate Fork Protection?mentioning

confidence: 99%

Monoubiquitination by the Fanconi Anemia core complex locks FANCI:FANCD2 on DNA in filamentous arrays

Tan

Twest

Leis

et al. 2019

Preprint

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FANCI:FANCD2 monoubiquitination is a critical event for replication fork stabilization by theFanconi anemia (FA) DNA repair pathway. It has been proposed that at stalled replication forks, monoubiquitinated-FANCD2 serves to recruit DNA repair proteins that contain ubiquitin-binding motifs. Here we have reconstituted the FA pathway in vitro to study functional consequences of FANCI:FANCD2 monoubiquitination. We report that monoubiquitination does not promote any specific exogenous protein:protein interactions, but instead stabilizes FANCI:FANCD2 heterodimers on dsDNA. This locking of FANCI:FANCD2 complex on DNA requires monoubiquitination of only the FANCD2 subunit. We further show that purified monoubiquitinated FANCI:FANCD2 forms filament-like arrays on long dsDNA using electron microscopy. Our results reveal how monoubiquitinated FANCI:FANCD2 is activated upon DNA binding and present new insights to potentially modulate monoubiquitinated FANCI:FANCD2/DNA filaments in FA cells. Fanconi Anemia | ubiquitination | DNA repair | biochemistry

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Interdependence of bacterial cell division and genome segregation and its potential in drug development

Cited by 18 publications

References 183 publications

Conditional Silencing by CRISPRi Reveals the Role of DNA Gyrase in Formation of Drug-Tolerant Persister Population in Mycobacterium tuberculosis

Conditional Silencing by CRISPRi Reveals the Role of DNA Gyrase in Formation of Drug-Tolerant Persister Population in Mycobacterium tuberculosis

The key bacterial cell division protein FtsZ as a novel antibacterial drug target

Monoubiquitination by the Fanconi Anemia core complex locks FANCI:FANCD2 on DNA in filamentous arrays

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