Global Assessment of Genomic Regions Required for Growth in Mycobacterium tuberculosis

Zhang, Yanjia Jason; Ioerger, Thomas R.; Huttenhower, Curtis; Long, Jarukit E.; Sassetti, Christopher M.; Sacchettini, James C.; Rubín, Eric J.

doi:10.1371/journal.ppat.1002946

Cited by 220 publications

(239 citation statements)

References 26 publications

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“…The deletion was verified by PCR ( Fig. 5B and C), confirming the previous prediction that the gene is not essential (53), and the absence of rv0634A mRNA was verified by RT-qPCR (Fig. 5D).…”

Section: Resultssupporting

confidence: 87%

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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Section: Resultssupporting

confidence: 87%

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

et al. 2015

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“…2, middle gray circle). Lastly, a statistical test described previously (29) was used to identify regions with significantly reduced diversity compared with the remainder of the genome (Fig. 2, outer gray circle).…”

Section: Resultsmentioning

confidence: 99%

“…SNP density was analyzed using the method described previously (29) to identify and calculate q values for low density regions. SNP density was analyzed in a sliding window analysis, with 100-bp window sizes and 25-bp step sizes.…”

Section: Methodsmentioning

confidence: 99%

Limits and patterns of cytomegalovirus genomic diversity in humans

Renzette

Pokalyuk

Gibson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

112

129

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Human cytomegalovirus (HCMV) exhibits surprisingly high genomic diversity during natural infection although little is known about the limits or patterns of HCMV diversity among humans. To address this deficiency, we analyzed genomic diversity among congenitally infected infants. We show that there is an upper limit to HCMV genomic diversity in these patient samples, with ∼25% of the genome being devoid of polymorphisms. These low diversity regions were distributed across 26 loci that were preferentially located in DNA-processing genes. Furthermore, by developing, to our knowledge, the first genome-wide mutation and recombination rate maps for HCMV, we show that genomic diversity is positively correlated with these two rates. In contrast, median levels of viral genomic diversity did not vary between putatively single or mixed strain infections. We also provide evidence that HCMV populations isolated from vascular compartments of hosts from different continents are genetically similar and that polymorphisms in glycoproteins and regulatory proteins are enriched in these viral populations. This analysis provides the most highly detailed map of HCMV genomic diversity in human hosts to date and informs our understanding of the distribution of HCMV genomic diversity within human hosts.human cytomegalovirus | HCMV | congenital CMV | virology | evolution

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“…Both pathways share the reactions catalyzed by NadE and nicotinic acid mononucleotide adenylyltransferase (encoded by nadD) (24,25). Transposon mutagenesis identified nadD and nadE as required for optimal in vitro growth (26,27). This essentiality for replication so far precluded an analysis of their requirement for viability in nonreplicating or slowly replicating Mtb such as those associated with the chronic phase of infection.…”

Section: Consequences Of Inactivating Nade For Growth and Survival Ofmentioning

confidence: 99%

A genetic strategy to identify targets for the development of drugs that prevent bacterial persistence

Kim

O’Brien

Sharma

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

136

152

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Antibacterial drug development suffers from a paucity of targets whose inhibition kills replicating and nonreplicating bacteria. The latter include phenotypically dormant cells, known as persisters, which are tolerant to many antibiotics and often contribute to failure in the treatment of chronic infections. This is nowhere more apparent than in tuberculosis caused by Mycobacterium tuberculosis, a pathogen that tolerates many antibiotics once it ceases to replicate. We developed a strategy to identify proteins that Mycobacterium tuberculosis requires to both grow and persist and whose inhibition has the potential to prevent drug tolerance and persister formation. This strategy is based on a tunable dualcontrol genetic switch that provides a regulatory range spanning three orders of magnitude, quickly depletes proteins in both replicating and nonreplicating mycobacteria, and exhibits increased robustness to phenotypic reversion. Using this switch, we demonstrated that depletion of the nicotinamide adenine dinucleotide synthetase (NadE) rapidly killed Mycobacterium tuberculosis under conditions of standard growth and nonreplicative persistence induced by oxygen and nutrient limitation as well as during the acute and chronic phases of infection in mice. These findings establish the dual-control switch as a robust tool with which to probe the essentiality of Mycobacterium tuberculosis proteins under different conditions, including those that induce antibiotic tolerance, and NadE as a target with the potential to shorten current tuberculosis chemotherapies.

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Global Assessment of Genomic Regions Required for Growth in Mycobacterium tuberculosis

Cited by 220 publications

References 26 publications

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

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

Limits and patterns of cytomegalovirus genomic diversity in humans

A genetic strategy to identify targets for the development of drugs that prevent bacterial persistence

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