Universal access to care for multidrug-resistant tuberculosis: an analysis of surveillance data

Falzon, Dennis; Jaramillo, Ernesto; Wares, Fraser; Zignol, Matteo; Floyd, Katherine; Raviglione, Mario

doi:10.1016/s1473-3099(13)70130-0

Cited by 73 publications

(65 citation statements)

References 16 publications

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“…10 Despite a well-developed public health system, many populations in India remain either underserved or without access to the health services available from the public health facilities. [11][12][13][14] To enhance access to care and create an equitable distribution of health services across the country, the government of India created the National Rural Health Mission (NHRM). The NRHM has undertaken many initiatives to provide health care to underserved populations, including providing one mobile medical unit (MMU) in each district to increase the accessibility of public health services, especially in remote or difficult-to-reach locations.…”

mentioning

confidence: 99%

Screening difficult-to-reach populations for tuberculosis using a mobile medical unit, Punjab India

Binepal¹,

Agarwal²,

Kaur³

et al. 2015

public health action

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mentioning

confidence: 99%

Screening difficult-to-reach populations for tuberculosis using a mobile medical unit, Punjab India

Binepal¹,

Agarwal²,

Kaur³

et al. 2015

public health action

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“…With 8.7 million new cases, 1.45 million deaths in 2011 alone 13 , and emergence of multidrug-resistant tuberculosis (TB) 14 , Mtb has re-emerged as an enormous challenge to public health system worldwide. Moreover, TB and HIV co-infection 15 , and the appearance of extensively drug-resistant TB 16 have necessitated intense on-going search for novel drug targets 17 and new drugs 18 .…”

mentioning

confidence: 99%

Targeting Mycobacterium tuberculosis nucleoid-associated protein HU with structure-based inhibitors

et al. 2014

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The nucleoid-associated protein HU plays an important role in maintenance of chromosomal architecture and in global regulation of DNA transactions in bacteria. Although HU is essential for growth in Mycobacterium tuberculosis (Mtb), there have been no reported attempts to perturb HU function with small molecules. Here we report the crystal structure of the N-terminal domain of HU from Mtb. We identify a core region within the HU-DNA interface that can be targeted using stilbene derivatives. These small molecules specifically inhibit HU-DNA binding, disrupt nucleoid architecture and reduce Mtb growth. The stilbene inhibitors induce gene expression changes in Mtb that resemble those induced by HU deficiency. Our results indicate that HU is a potential target for the development of therapies against tuberculosis.

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“…A long-standing challenge to the fight against tuberculosis is the ability of the pathogen to develop a nonreplicating, persistent, drug-tolerant form (1)(2)(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 targets through a better understanding of the genetic programs developed by the bacterium to enable infection.…”

mentioning

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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Universal access to care for multidrug-resistant tuberculosis: an analysis of surveillance data

Cited by 73 publications

References 16 publications

Screening difficult-to-reach populations for tuberculosis using a mobile medical unit, Punjab India

Screening difficult-to-reach populations for tuberculosis using a mobile medical unit, Punjab India

Targeting Mycobacterium tuberculosis nucleoid-associated protein HU with structure-based inhibitors

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

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