scholarly journals From infection niche to therapeutic target: the intracellular lifestyle of Mycobacterium tuberculosis

Microbiology ◽  
2021 ◽  
Vol 167 (4) ◽  
Author(s):  
Leah Isobella Rankine-Wilson ◽  
Tirosh Shapira ◽  
Carine Sao Emani ◽  
Yossef Av-Gay
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Side Effects ◽  
Type Species ◽  
Life Stage ◽  
Maturation Process ◽  
Human Pathogen ◽  
Phagosome Maturation ◽  
Content Type ◽  
The Past ◽  
Multiple Drugs

Mycobacterium tuberculosis (Mtb) is an obligate human pathogen killing millions of people annually. Treatment for tuberculosis is lengthy and complicated, involving multiple drugs and often resulting in serious side effects and non-compliance. Mtb has developed numerous complex mechanisms enabling it to not only survive but replicate inside professional phagocytes. These mechanisms include, among others, overcoming the phagosome maturation process, inhibiting the acidification of the phagosome and inhibiting apoptosis. Within the past decade, technologies have been developed that enable a more accurate understanding of Mtb physiology within its intracellular niche, paving the way for more clinically relevant drug-development programmes. Here we review the molecular biology of Mtb pathogenesis offering a unique perspective on the use and development of therapies that target Mtb during its intracellular life stage.

scholarly journals Global transcriptome analysis of Stenotrophomonas maltophilia in response to growth at human body temperature

2021 ◽  
Vol 7 (7) ◽  
Author(s):  
Prashant P. Patil ◽  
Sanjeet Kumar ◽  
Amandeep Kaur ◽  
Samriti Midha ◽  
Kanika Bansal ◽  
...  
Keyword(s):  
Body Temperature ◽  
Human Body ◽  
Transcriptome Analysis ◽  
Stenotrophomonas Maltophilia ◽  
Type Species ◽  
Human Pathogen ◽  
Content Type ◽  
Link Type ◽  
Human Body Temperature ◽  
Opportunistic Human Pathogen

Stenotrophomonas maltophilia is a typical example of an environmental originated opportunistic human pathogen, which can thrive at different habitats including the human body and can cause a wide range of infections. It must cope with heat stress during transition from the environment to the human body as the physiological temperature of the human body (37 °C) is higher than environmental niches (22–30 °C). Interestingly, S. rhizophila a phylogenetic neighbour of S. maltophilia within genus Stenotrophomonas is unable to grow at 37 °C. Thus, it is crucial to understand how S. maltophilia is adapted to human body temperature, which could suggest its evolution as an opportunistic human pathogen. In this study, we have performed comparative transcriptome analysis of S. maltophilia grown at 28 and 37 °C as temperature representative for environmental niches and the human body, respectively. RNA-Seq analysis revealed several interesting findings showing alterations in gene-expression levels at 28 and 37 °C, which can play an important role during infection. We have observed downregulation of genes involved in cellular motility, energy production and metabolism, replication and repair whereas upregulation of VirB/D4 type IV secretion system, aerotaxis, cation diffusion facilitator family transporter and LacI family transcriptional regulators at 37 °C. Microscopy and plate assays corroborated altered expression of genes involved in motility. The results obtained enhance our understanding of the strategies employed by S. maltophilia during adaptation towards the human body.

Biochemical and functional characterization of Mycobacterium tuberculosis ketol-acid reductoisomerase

Microbiology ◽  
2021 ◽  
Vol 167 (9) ◽  
Author(s):  
Nirbhay Singh ◽  
Anu Chauhan ◽  
Ram Kumar ◽  
Sudheer Kumar Singh
Keyword(s):  
Amino Acids ◽  
Mycobacterium Tuberculosis ◽  
Type Species ◽  
Low Ph ◽  
Stress Conditions ◽  
Starvation Stress ◽  
Content Type ◽  
E Coli ◽  
Link Type

Branched-chain amino acids (BCAAs) are essential amino acids, but their biosynthetic pathway is absent in mammals. Ketol-acid reductoisomerase (IlvC) is a BCAA biosynthetic enzyme that is coded by Rv3001c in Mycobacterium tuberculosis H37Rv (Mtb-Rv) and MRA_3031 in M. tuberculosis H37Ra (Mtb-Ra). IlvCs are essential in Mtb-Rv as well as in Escherichia coli . Compared to wild-type and IlvC-complemented Mtb-Ra strains, IlvC knockdown strain showed reduced survival at low pH and under low pH+starvation stress conditions. Further, increased expression of IlvC was observed under low pH and starvation stress conditions. Confirmation of a role for IlvC in pH and starvation stress was achieved by developing E. coli BL21(DE3) IlvC knockout, which was defective for growth in M9 minimal medium, but growth could be rescued by isoleucine and valine supplementation. Growth was also restored by complementing with over-expressing constructs of Mtb-Ra and E. coli IlvCs. The E. coli knockout also had a survival deficit at pH=5.5 and 4.5 and was more susceptible to killing at pH=3.0. The biochemical characterization of Mtb-Ra and E. coli IlvCs confirmed that both have NADPH-dependent activity. In conclusion, this study demonstrates the functional complementation of E. coli IlvC by Mtb-Ra IlvC and also suggests that IlvC has a role in tolerance to low pH and starvation stress.

scholarly journals Roles for phthiocerol dimycocerosate lipids in Mycobacterium tuberculosis pathogenesis

Microbiology ◽  
2021 ◽  
Author(s):  
Céline Rens ◽  
Joseph D. Chao ◽  
Danielle L. Sexton ◽  
Elitza I. Tocheva ◽  
Yossef Av-Gay
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Type Species ◽  
Cell Envelope ◽  
Infectious Agent ◽  
Resistant Bacteria ◽  
Content Type ◽  
Link Type ◽  
Drug Resistant Bacteria ◽  
Macrophage Phagocytosis ◽  
Key Steps

The success of Mycobacterium tuberculosis as a pathogen is well established: tuberculosis is the leading cause of death by a single infectious agent worldwide. The threat of multi- and extensively drug-resistant bacteria has renewed global concerns about this pathogen and understanding its virulence strategies will be essential in the fight against tuberculosis. The current review will focus on phthiocerol dimycocerosates (PDIMs), a long-known and well-studied group of complex lipids found in the M. tuberculosis cell envelope. Numerous studies show a role for PDIMs in several key steps of M. tuberculosis pathogenesis, with recent studies highlighting its involvement in bacterial virulence, in association with the ESX-1 secretion system. Yet, the mechanisms by which PDIMs help M. tuberculosis to control macrophage phagocytosis, inhibit phagosome acidification and modulate host innate immunity, remain to be fully elucidated.

scholarly journals Molecular detection of Mycobacterium tuberculosis in poor-quality cough specimens

2020 ◽  
Vol 69 (9) ◽  
pp. 1179-1182
Author(s):  
Tondani A. Mboneni ◽  
Owen O. Eales ◽  
Ntsoaki L. Mosina ◽  
P. Bernard Fourie
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Type Species ◽  
Molecular Detection ◽  
Molecular Transport ◽  
Poor Quality ◽  
Rt Pcr ◽  
Missed Opportunities ◽  
Content Type ◽  
Clinical Specimens ◽  
Enhanced Sensitivity

Clinical specimens unfit for laboratory processing represent missed opportunities for diagnosing tuberculosis. Poor-quality cough specimens (n=61) from presumptive tuberculosis cases were cultured and GeneXpert MTB/RIF (Xpert) successfully performed on samples transferred by flocked swab into PrimeStore molecular transport medium (PS-MTM). Mycobacterium tuberculosis was grown in culture from 13 (21.3 %) and Xpert reported 15 (24.2 %) positive, of which 10 concordant. RT-PCR of PS-MTM samples showed enhanced sensitivity; three positives were missed by Xpert, five by culture and three more detected for a total of 21 positives (34.4 %).

scholarly journals Revised nomenclature and SNP barcode for Mycobacterium tuberculosis lineage 2

2021 ◽  
Vol 7 (11) ◽  
Author(s):  
Yuttapong Thawornwattana ◽  
Surakameth Mahasirimongkol ◽  
Hideki Yanai ◽  
Htet Myat Win Maung ◽  
Zhezhe Cui ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Type Species ◽  
Classification Scheme ◽  
Snp Markers ◽  
Drug Resistant ◽  
Fine Scale ◽  
Content Type ◽  
Classification Schemes ◽  
Disease Epidemiology ◽  
Lineage 2

Mycobacterium tuberculosis (Mtb) lineage 2 (L2) strains are present globally, contributing to a widespread tuberculosis (TB) burden, particularly in Asia where both prevalence of TB and numbers of drug resistant TB are highest. The increasing availability of whole-genome sequencing (WGS) data worldwide provides an opportunity to improve our understanding of the global genetic diversity of Mtb L2 and its association with the disease epidemiology and pathogenesis. However, existing L2 sublineage classification schemes leave >20 % of the Modern Beijing isolates unclassified. Here, we present a revised SNP-based classification scheme of L2 in a genomic framework based on phylogenetic analysis of >4000 L2 isolates from 34 countries in Asia, Eastern Europe, Oceania and Africa. Our scheme consists of over 30 genotypes, many of which have not been described before. In particular, we propose six main genotypes of Modern Beijing strains, denoted L2.2.M1–L2.2.M6. We also provide SNP markers for genotyping L2 strains from WGS data. This fine-scale genotyping scheme, which can classify >98 % of the studied isolates, serves as a basis for more effective monitoring and reporting of transmission and outbreaks, as well as improving genotype-phenotype associations such as disease severity and drug resistance. This article contains data hosted by Microreact.

scholarly journals Endemic fluoroquinolone-resistant Salmonella enterica serovar Kentucky ST198 in northern India

2019 ◽  
Vol 5 (7) ◽  
Author(s):  
Jaspreet Mahindroo ◽  
Duy Pham Thanh ◽  
To Nguyen Thi Nguyen ◽  
Balvinder Mohan ◽  
Siddhartha Thakur ◽  
...  
Keyword(s):  
North America ◽  
Middle East ◽  
South Asia ◽  
Salmonella Enterica ◽  
Type Species ◽  
Human Infection ◽  
Human Pathogen ◽  
Epidemic Clone ◽  
Content Type ◽  
Northern India

Salmonella e nterica serovar Kentucky is an emergent human pathogen. Human infection with ciprofloxacin-resistant S. enterica Kentucky ST198 has been reported in Europe and North America as a consequence of travel to Asia/the Middle East. This is, to the best of our knowledge, the first study reporting the identification of this epidemic clone in India and South Asia.

scholarly journals Phenolic Compounds as Promising Drug Candidates in Tuberculosis Therapy

Molecules ◽  
2019 ◽  
Vol 24 (13) ◽  
pp. 2449
Author(s):  
Muhamad Harith Mazlun ◽  
Siti Fatimah Sabran ◽  
Maryati Mohamed ◽  
Mohd Fadzelly Abu Bakar ◽  
Zunoliza Abdullah
Keyword(s):  
Natural Products ◽  
Mycobacterium Tuberculosis ◽  
Phenolic Compounds ◽  
Side Effects ◽  
Drug Candidates ◽  
The Past ◽  
Test Organisms ◽  
Tuberculosis Therapy ◽  
Emergence Of Resistance

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB) remains one of the deadliest, infectious diseases worldwide. The detrimental effects caused by the existing anti-TB drugs to TB patients and the emergence of resistance strains of M. tuberculosis has driven efforts from natural products researchers around the globe in discovering novel anti-TB drugs that are more efficacious and with less side effects. There were eleven main review publications that focused on natural products with anti-TB potentials. However, none of them specifically emphasized antimycobacterial phenolic compounds. Thus, the current review’s main objective is to highlight and summarize phenolic compounds found active against mycobacteria from 2000 to 2017. Based on the past studies in the electronic databases, the present review also focuses on several test organisms used in TB researches and their different distinct properties, a few types of in vitro TB bioassay and comparison between their strengths and drawbacks, different methods of extraction, fractionation and isolation, ways of characterizing and identifying isolated compounds and the mechanism of actions of anti-TB phenolic compounds as reported in the literature.

scholarly journals Pyrazinamide Is Active against Mycobacterium tuberculosis Cultures at Neutral pH and Low Temperature

2016 ◽  
Vol 60 (8) ◽  
pp. 4956-4960 ◽  
Author(s):  
Alice L. den Hertog ◽  
Sandra Menting ◽  
Richard Pfeltz ◽  
Matthew Warns ◽  
Salman H. Siddiqi ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Low Temperature ◽  
Susceptibility Testing ◽  
Drug Susceptibility ◽  
Drug Susceptibility Testing ◽  
Acidic Ph ◽  
Content Type ◽  
The Past ◽  
Neutral Ph

ABSTRACTFor the past decades, an acidic pH has been used to renderMycobacterium tuberculosissusceptible to pyrazinamide forin vitrotesting. Here, we show that at the standard breakpoint concentration and reduced culture temperatures, pyrazinamide (PZA) is active against tuberculosis (TB) at neutral pH. This finding should help unravel the mechanism of action of PZA and allow drug susceptibility testing (DST) methods to be optimized.

scholarly journals The Copper-Responsive RicR Regulon Contributes to Mycobacterium tuberculosis Virulence

mBio ◽  
2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Xiaoshan Shi ◽  
Richard A. Festa ◽  
Thomas R. Ioerger ◽  
Susan Butler-Wu ◽  
James C. Sacchettini ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Microbial Growth ◽  
Human Pathogen ◽  
Content Type ◽  
Cu Toxicity ◽  
Cu Homeostasis ◽  
Cu Resistance ◽  
Life On Earth

ABSTRACTAs with most life on Earth, the transition metal copper (Cu) is essential for the viability of the human pathogenMycobacterium tuberculosis. However, infected hosts can also use Cu to control microbial growth. Several Cu-responsive pathways are present inM. tuberculosis, including the regulated in copper repressor (RicR) regulon, which is unique to pathogenic mycobacteria. In this work, we describe the contribution of each RicR-regulated gene to Cu resistancein vitroand to virulence in animals. We found that the deletion or disruption of individual RicR-regulated genes had no impact on virulence in mice, although several mutants had Cu hypersensitivity. In contrast, a mutant unable to activate the RicR regulon was not only highly susceptible to Cu but also attenuated in mice. Thus, these data suggest that several genes of the RicR regulon are required simultaneously to combat Cu toxicityin vivoor that this regulon is also important for resistance against Cu-independent mechanisms of host defense.IMPORTANCEMycobacterium tuberculosisis the causative agent of tuberculosis, killing millions of people every year. Therefore, understanding the biology ofM. tuberculosisis crucial for the development of new therapies to treat this devastating disease. Our studies reveal that although host-supplied Cu can suppress bacterial growth,M. tuberculosishas a unique pathway, the RicR regulon, to defend against Cu toxicity. These findings suggest that Cu homeostasis pathways in both the host and the pathogen could be exploited for the treatment of tuberculosis.

scholarly journals Methicillin-ResistantStaphylococcus aureus: Molecular Characterization, Evolution, and Epidemiology

2018 ◽  
Vol 31 (4) ◽  
Author(s):  
Sahreena Lakhundi ◽  
Kunyan Zhang
Keyword(s):  
Molecular Characterization ◽  
Classification Criteria ◽  
Human Pathogen ◽  
Community Settings ◽  
Content Type ◽  
The Past ◽  
Typing Methods ◽  
Historical Methods ◽  
Shed Light ◽  
Staphylococcal Cassette Chromosome

SUMMARYStaphylococcus aureus, a major human pathogen, has a collection of virulence factors and the ability to acquire resistance to most antibiotics. This ability is further augmented by constant emergence of new clones, makingS. aureusa “superbug.” Clinical use of methicillin has led to the appearance of methicillin-resistantS. aureus(MRSA). The past few decades have witnessed the existence of new MRSA clones. Unlike traditional MRSA residing in hospitals, the new clones can invade community settings and infect people without predisposing risk factors. This evolution continues with the buildup of the MRSA reservoir in companion and food animals. This review focuses on imparting a better understanding of MRSA evolution and its molecular characterization and epidemiology. We first describe the origin of MRSA, with emphasis on the diverse nature of staphylococcal cassette chromosomemec(SCCmec).mecAand its new homologues (mecB,mecC, andmecD), SCCmectypes (13 SCCmectypes have been discovered to date), and their classification criteria are discussed. The review then describes various typing methods applied to study the molecular epidemiology and evolutionary nature of MRSA. Starting with the historical methods and continuing to the advanced whole-genome approaches, typing of collections of MRSA has shed light on the origin, spread, and evolutionary pathways of MRSA clones.

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