Medical Abstracts

Keyword: tuberculosis

1. Nature. 2019 Jul;571(7763):72-78. doi: 10.1038/s41586-019-1315-z. Epub 2019 Jun 19.

Large-scale chemical-genetics yields new M. tuberculosis inhibitor classes.

Johnson EO(1)(2)(3), LaVerriere E(1)(4), Office E(1), Stanley M(1)(5), Meyer

E(1)(6), Kawate T(1)(2)(3), Gomez JE(1), Audette RE(7)(8), Bandyopadhyay N(1),

Betancourt N(9)(10), Delano K(1), Da Silva I(9), Davis J(1)(11), Gallo C(1)(12),

Gardner M(7), Golas AJ(1), Guinn KM(7), Kennedy S(1), Korn R(1), McConnell JA(9),

Moss CE(13)(14), Murphy KC(13), Nietupski RM(1), Papavinasasundaram KG(13),

Pinkham JT(7), Pino PA(9), Proulx MK(13), Ruecker N(9), Song N(9), Thompson

M(1)(15), Trujillo C(9), Wakabayashi S(7), Wallach JB(9), Watson C(1)(16),

Ioerger TR(17), Lander ES(1), Hubbard BK(1), Serrano-Wu MH(1), Ehrt S(9),

Fitzgerald M(1), Rubin EJ(7), Sassetti CM(13), Schnappinger D(9), Hung

DT(18)(19)(20).

Author information:

(1)Broad Institute of MIT and Harvard, Cambridge, MA, USA.

(2)Department of Molecular Biology and Center for Computational and Integrative

Biology, Massachusetts General Hospital, Boston, MA, USA.

(3)Department of Genetics, Harvard Medical School, Boston, MA, USA.

...

New antibiotics are needed to combat rising levels of resistance, with new

Mycobacterium tuberculosis (Mtb) drugs having the highest priority. However,

conventional whole-cell and biochemical antibiotic screens have failed. Here we

develop a strategy termed PROSPECT (primary screening of strains to prioritize

expanded chemistry and targets), in which we screen compounds against pools of

strains depleted of essential bacterial targets. We engineered strains that

target 474 essential Mtb genes and screened pools of 100-150 strains against

activity-enriched and unbiased compound libraries, probing more than 8.5 million

chemical-genetic interactions. Primary screens identified over tenfold more hits

than screening wild-type Mtb alone, with chemical-genetic interactions providing

immediate, direct target insights. We identified over 40 compounds that target

DNA gyrase, the cell wall, tryptophan, folate biosynthesis and RNA polymerase, as

well as inhibitors that target EfpA. Chemical optimization yielded EfpA

inhibitors with potent wild-type activity, thus demonstrating the ability of

PROSPECT to yield inhibitors against targets that would have eluded conventional

drug discovery.

DOI: 10.1038/s41586-019-1315-z

PMID: 31217586

2. Nature. 2019 Jun;570(7762):528-532. doi: 10.1038/s41586-019-1276-2. Epub 2019 Jun 5.

Group 3 innate lymphoid cells mediate early protective immunity against

tuberculosis.

Ardain A(1)(2), Domingo-Gonzalez R(3), Das S(3), Kazer SW(4)(5)(6), Howard NC(3),

Singh A(1)(2), Ahmed M(3), Nhamoyebonde S(1)(2), Rangel-Moreno J(7), Ogongo

P(1)(2)(8), Lu L(3), Ramsuran D(2), de la Luz Garcia-Hernandez M(7), Ulland

TK(9), Darby M(10), Park E(9)(11), Karim F(1), Melocchi L(9), Madansein R(12),

Dullabh KJ(12), Dunlap M(3), Marin-Agudelo N(3), Ebihara T(9)(11), Ndung'u

T(1)(2), Kaushal D(13), Pym AS(1)(2), Kolls JK(14), Steyn A(1)(2)(15), Zúñiga

J(16)(17), Horsnell W(10)(18), Yokoyama WM(9)(11)(19), Shalek AK(4)(5)(6),

Kløverpris HN(1)(2)(20)(21), Colonna M(9), Leslie A(22)(23)(24), Khader SA(25).

Author information:

(1)Africa Health Research Institute, Durban, South Africa.

(2)School of Laboratory Medicine and Medical Sciences, University of

KwaZulu-Natal, Durban, South Africa.

(3)Department of Molecular Microbiology, Washington University School of

Medicine, St Louis, MO, USA.

...

Erratum in

Nature. 2019 Jul 24;:.

Tuberculosis is the leading cause of death by an infectious disease worldwide1.

However, the involvement of innate lymphoid cells (ILCs) in immune responses to

infection with Mycobacterium tuberculosis (Mtb) is unknown. Here we show that

circulating subsets of ILCs are depleted from the blood of participants with

pulmonary tuberculosis and restored upon treatment. Tuberculosis increased

accumulation of ILC subsets in the human lung, coinciding with a robust

transcriptional response to infection, including a role in orchestrating the

recruitment of immune subsets. Using mouse models, we show that group 3 ILCs

(ILC3s) accumulated rapidly in Mtb-infected lungs and coincided with the

accumulation of alveolar macrophages. Notably, mice that lacked ILC3s exhibited a

reduction in the accumulation of early alveolar macrophages and decreased Mtb

control. We show that the C-X-C motif chemokine receptor 5 (CXCR5)-C-X-C motif

chemokine ligand 13 (CXCL13) axis is involved in Mtb control, as infection

upregulates CXCR5 on circulating ILC3s and increases plasma levels of its ligand,

CXCL13, in humans. Moreover, interleukin-23-dependent expansion of ILC3s in mice

and production of interleukin-17 and interleukin-22 were found to be critical

inducers of lung CXCL13, early innate immunity and the formation of protective

lymphoid follicles within granulomas. Thus, we demonstrate an early protective

role for ILC3s in immunity to Mtb infection.

DOI: 10.1038/s41586-019-1276-2

PMCID: PMC6626542 [Available on 2019-12-05]

PMID: 31168092

3. Lancet Infect Dis. 2019 Jun 17. pii: S1473-3099(18)30787-4. doi:

10.1016/S1473-3099(18)30787-4. [Epub ahead of print]

The evolving research agenda for paediatric tuberculosis infection.

Seddon JA(1), Whittaker E(2), Kampmann B(3), Lewinsohn DA(4), Osman M(5),

Hesseling AC(5), Rustomjee R(6), Amanullah F(7).

Author information:

(1)Academic Department of Paediatrics, Imperial College London, London, UK;

Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of

Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Electronic address: james.seddon@imperial.ac.uk.

(2)Academic Department of Paediatrics, Imperial College London, London, UK.

(3)The Vaccine Centre, Faculty of Infectious and Tropical Diseases, London School

of Hygiene & Tropical Medicine, London, UK; MRC Unit The Gambia at the London

School of Hygiene and Tropical Medicine, The Gambia.

...

Following exposure to tuberculosis and subsequent infection, children often

progress to tuberculosis disease more rapidly than adults. And yet the natural

history of tuberculosis in children, as a continuum from exposure to infection

and then to disease, is poorly understood. Children are rarely diagnosed with

tuberculosis infection in routine care in international settings and few receive

tuberculosis infection treatment. In this Personal View, we review the most

up-to-date knowledge in three areas of childhood tuberculosis infection-namely,

pathophysiology, diagnosis, and treatment. We then outline what is missing in

each of these three areas to generate a priority research agenda. Finally, we

suggest potential study designs that might answer these questions. Understanding

of pathophysiology could be improved through animal models, laboratory studies

assessing the immunological responses of blood or respiratory samples to

Mycobacterium spp in vitro, as well as investigating immune responses in children

exposed to tuberculosis. Identification of children with sub-clinical disease and

at high risk of progression to clinically overt disease, would allow treatment to

be targeted at those most likely to benefit. Optimisation and discovery of novel

treatments for tuberculosis infection in children should account for mechanisms

of action of tuberculosis drugs, as well as child-specific factors including

pharmacokinetics and appropriate formulations. To conduct these studies, a change

in mindset is required, with a recognition that the diagnosis and treatment of

tuberculosis infection in children is a necessary component in addressing the

overall tuberculosis epidemic. Collaboration between stakeholders will be

required and funding will need to increase, both for research and implementation.

The consequences of inaction, however, will lead to further decades of children

suffering from what should increasingly be recognised as a preventable disease.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(18)30787-4

PMID: 31221543

4. FEMS Microbiol Rev. 2019 Jun 10. pii: fuz016. doi: 10.1093/femsre/fuz016. [Epub

ahead of print]

Cell wall peptidoglycan in Mycobacterium tuberculosis: An Achilles' heel for the

TB-causing pathogen.

Maitra A(1), Munshi T(1), Healy J(2), Martin LT(1), Vollmer W(3), Keep NH(1),

Bhakta S(1).

Author information:

(1)Mycobacteria Research Laboratory, Institute of Structural and Molecular

Biology, Department of Biological Sciences, Birkbeck, University of London, Malet

Street, London WC1E 7HX, UK.

(2)Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy,

29-39 Brunswick Square, London WC1N 1AX, UK.

(3)The Centre for Bacterial Cell Biology, Institute for Cell and Molecular

Biosciences, Newcastle University, Richardson Road, Newcastle upon Tyne, NE2 4AX,

UK.

Tuberculosis (TB), caused by the intracellular pathogen Mycobacterium

tuberculosis, remains one of the leading causes of mortality across the world.

There is an urgent requirement to build a robust arsenal of effective

antimicrobials, targeting novel molecular mechanisms to overcome the challenges

posed by the increase of antibiotic resistance in TB. M. tuberculosis has a

unique cell envelope structure and composition, containing a peptidoglycan layer

that is essential for maintaining cellular integrity and for virulence. The

enzymes involved in the biosynthesis, degradation, remodelling and recycling of

peptidoglycan have resurfaced as attractive targets for anti-infective drug

discovery. Here we review the importance of peptidoglycan, including the

structure, function and regulation of key enzymes involved in its metabolism. We

also discuss known inhibitors against ATP-dependent Mur ligases, and discuss the

potential for the development of pan-enzyme inhibitors targeting multiple Mur

ligases.

© FEMS 2019.

DOI: 10.1093/femsre/fuz016

PMID: 31183501

5. Nat Commun. 2019 Jun 6;10(1):2480. doi: 10.1038/s41467-019-10447-y.

Introducing risk inequality metrics in tuberculosis policy development.

Gomes MGM(1)(2), Oliveira JF(3), Bertolde A(4), Ayabina D(5), Nguyen TA(6),

Maciel EL(7), Duarte R(8), Nguyen BH(6), Shete PB(9), Lienhardt C(10)(11).

Author information:

(1)Liverpool School of Tropical Medicine, Liverpool, L3 5QA, United Kingdom.

gabriela.gomes@lstmed.ac.uk.

(2)CIBIO-InBIO, Centro de Investigação em Biodiversidade e Recursos Genéticos,

Universidade do Porto, Vairão, 4485-661, Portugal. gabriela.gomes@lstmed.ac.uk.

(3)CIBIO-InBIO, Centro de Investigação em Biodiversidade e Recursos Genéticos,

Universidade do Porto, Vairão, 4485-661, Portugal.

...

Global stakeholders including the World Health Organization rely on predictive

models for developing strategies and setting targets for tuberculosis care and

control programs. Failure to account for variation in individual risk leads to

substantial biases that impair data interpretation and policy decisions.

Anticipated impediments to estimating heterogeneity for each parameter are

discouraging despite considerable technical progress in recent years. Here we

identify acquisition of infection as the single process where heterogeneity most

fundamentally impacts model outputs, due to selection imposed by dynamic forces

of infection. We introduce concrete metrics of risk inequality, demonstrate their

utility in mathematical models, and pack the information into a risk inequality

coefficient (RIC) which can be calculated and reported by national tuberculosis

programs for use in policy development and modeling.

DOI: 10.1038/s41467-019-10447-y

PMCID: PMC6554307

PMID: 31171791 [Indexed for MEDLINE]

6. Chem Sci. 2019 May 16;10(23):5935-5942. doi: 10.1039/c9sc00415g. eCollection 2019 Jun 21.

Targeting extracellular glycans: tuning multimeric boronic acids for

pathogen-selective killing of Mycobacterium tuberculosis.

Guy CS(1)(2), Gibson MI(2)(3), Fullam E(1).

Author information:

(1)School of Life Sciences , University of Warwick , CV4 7AL , UK . Email:

e.fullam@warwick.ac.uk.

(2)Department of Chemistry , University of Warwick , Coventry , CV4 7AL , UK .

Email: m.i.gibson@warwick.ac.uk.

(3)Warwick Medical School , University of Warwick , Coventry , CV4 7AL , UK.

Innovative chemotherapeutic agents that are active against Mycobacterium

tuberculosis (Mtb) are urgently required to control the tuberculosis (TB)

epidemic. The Mtb cell envelope has distinct (lipo)polysaccharides and

glycolipids that play a critical role in Mtb survival and pathogenesis and

disruption of pathways involved in the assembly of the Mtb cell envelope are the

primary target of anti-tubercular agents. Here we introduce a previously

unexplored approach whereby chemical agents directly target the extracellular

glycans within the unique Mtb cell envelope, rather than the intracellular

biosynthetic machinery. We designed and synthesised multimeric boronic acids that

are selectively lethal to Mtb and function by targeting these structurally unique

and essential Mtb cell envelope glycans. By tuning the number of, and distance

between, boronic acid units high selectivity to Mtb, low cytotoxicity against

mammalian cells and no observable resistance was achieved. This non-conventional

approach may prevent the development of drug-resistance and will act as a

platform for the design of improved, pathogen-specific, next generation

antibiotics.

DOI: 10.1039/c9sc00415g

PMCID: PMC6566077

PMID: 31360399

7. J Immunol. 2019 Aug 15;203(4):972-980. doi: 10.4049/jimmunol.1900209. Epub 2019 Jun 28.

A Subset of Mycobacteria-Specific CD4+ IFN-γ+ T Cell Expressing Naive Phenotype

Confers Protection against Tuberculosis Infection in the Lung.

Yuan J(1), Tenant J(1), Pacatte T(1), Eickhoff C(1), Blazevic A(1), Hoft DF(1),

Chatterjee S(2).

Author information:

(1)Division of Infectious Diseases, Allergy and Immunology, Department of

Internal Medicine, Saint Louis University, St. Louis, MO 63104.

(2)Division of Infectious Diseases, Allergy and Immunology, Department of

Internal Medicine, Saint Louis University, St. Louis, MO 63104

soumyadoc@gmail.com.

Failure of the most recent tuberculosis (TB) vaccine trial to boost bacillus

Calmette-Guérin-mediated anti-TB immunity despite the induction of Th1-specific

central memory cell and effector memory cell responses highlights the importance

of identifying optimal T cell targets for protective vaccines. In this study, we

describe a novel, Mycobacterium tuberculosis-specific IFN-γ+CD4+ T cell

population expressing surface markers characteristic of naive-like memory T cells

(TNLM), which were induced in both human (CD45RA+CCR7+CD27+CD95-) and murine

(CD62L+CD44-Sca-1+CD122-) systems in response to mycobacteria. In bacillus

Calmette-Guérin-vaccinated subjects and those with latent TB infection, TNLM were

marked by the production of IFN-γ but not TNF-α and identified by the absence of

CD95 expression and increased surface expression CCR7, CD27, the activation

markers T-bet, CD69, and the survival marker CD74. Increased tetramer-positive

TNLM frequencies were noted in the lung and spleen of ESAT-61-20-specific TCR

transgenic mice at 2 wk postinfection with M. tuberculosis and progressively

decreased at later time points, a pattern not seen with TNF-α+CD4+ T cells

expressing naive cell surface markers. Importantly, adoptive transfer of highly

purified TNLM alone, from vaccinated ESAT-61-20-specific TCR transgenic mice,

conferred equivalent protection against M. tuberculosis infection in the lungs of

Rag-/- mice when compared with total memory populations (central and effector

memory cells). Thus, TNLM may represent a memory T cell population that, if

optimally targeted, may significantly improve future TB vaccine responses.

Copyright © 2019 by The American Association of Immunologists, Inc.

DOI: 10.4049/jimmunol.1900209

PMID: 31253726

8. J Immunol. 2019 Aug 15;203(4):922-935. doi: 10.4049/jimmunol.1900169. Epub 2019 Jun 24.

IL-36γ Promotes Killing of Mycobacterium tuberculosis by Macrophages via

WNT5A-Induced Noncanonical WNT Signaling.

Gao Y(1), Wen Q(1), Hu S(1), Zhou X(1), Xiong W(1), Du X(1), Zhang L(1), Fu Y(1),

Yang J(1), Zhou C(1), Zhang Z(1), Li Y(1), Liu H(1), Huang Y(1), Ma L(2).

Author information:

(1)Institute of Molecular Immunology, School of Laboratory Medicine and

Biotechnology, Southern Medical University, Guangzhou 510515, China.

(2)Institute of Molecular Immunology, School of Laboratory Medicine and

Biotechnology, Southern Medical University, Guangzhou 510515, China

maryhmz@126.com.

Mycobacterium tuberculosis, which primarily infects mononuclear phagocytes,

remains the leading bacterial cause of enormous morbidity and mortality because

of bacterial infections in humans throughout the world. The IL-1 family of

cytokines is critical for host resistance to M. tuberculosis As a newly

discovered subgroup of the IL-1 family, although IL-36 cytokines have been proven

to play roles in protection against M. tuberculosis infection, the antibacterial

mechanisms are poorly understood. In this study, we demonstrated that IL-36γ

conferred to human monocyte-derived macrophages bacterial resistance through

activation of autophagy as well as induction of WNT5A, a reported downstream

effector of IL-1 involved in several inflammatory diseases. Further studies

showed that WNT5A could enhance autophagy of monocyte-derived macrophages by

inducing cyclooxygenase-2 (COX-2) expression and in turn decrease phosphorylation

of AKT/mTOR via noncanonical WNT signaling. Consistently, the underlying

molecular mechanisms of IL-36γ function are also mediated by the COX-2/AKT/mTOR

signaling axis. Altogether, our findings reveal a novel activity for IL-36γ as an

inducer of autophagy, which represents a critical inflammatory cytokine that

control the outcome of M. tuberculosis infection in human macrophages.

Copyright © 2019 by The American Association of Immunologists, Inc.

DOI: 10.4049/jimmunol.1900169

PMCID: PMC6680068

PMID: 31235551

9. Proc Natl Acad Sci U S A. 2019 Jul 2;116(27):13573-13581. doi:

10.1073/pnas.1900176116. Epub 2019 Jun 19.

CarD contributes to diverse gene expression outcomes throughout the genome of

Mycobacterium tuberculosis.

Zhu DX(1), Garner AL(1), Galburt EA(2), Stallings CL(3).

Author information:

(1)Department of Molecular Microbiology, Washington University School of

Medicine, St. Louis, MO 63110.

(2)Department of Biochemistry and Molecular Biophysics, Washington University

School of Medicine, St. Louis, MO 63110.

(3)Department of Molecular Microbiology, Washington University School of

Medicine, St. Louis, MO 63110; stallings@wustl.edu.

The ability to regulate gene expression through transcription initiation

underlies the adaptability and survival of all bacteria. Recent work has revealed

that the transcription machinery in many bacteria diverges from the paradigm that

has been established in Escherichia coli Mycobacterium tuberculosis (Mtb) encodes

the RNA polymerase (RNAP)-binding protein CarD, which is absent in E. coli but is

required to form stable RNAP-promoter open complexes (RPo) and is essential for

viability in Mtb The stabilization of RPo by CarD has been proposed to result in

activation of gene expression; however, CarD has only been examined on limited

promoters that do not represent the typical promoter structure in Mtb In this

study, we investigate the outcome of CarD activity on gene expression from Mtb

promoters genome-wide by performing RNA sequencing on a panel of mutants that

differentially affect CarD's ability to stabilize RPo In all CarD mutants, the

majority of Mtb protein encoding transcripts were differentially expressed,

demonstrating that CarD had a global effect on gene expression. Contrary to the

expected role of CarD as a transcriptional activator, mutation of CarD led to

both up- and down-regulation of gene expression, suggesting that CarD can also

act as a transcriptional repressor. Furthermore, we present evidence that

stabilization of RPo by CarD could lead to transcriptional repression by

inhibiting promoter escape, and the outcome of CarD activity is dependent on the

intrinsic kinetic properties of a given promoter region. Collectively, our data

support CarD's genome-wide role of regulating diverse transcription outcomes.

DOI: 10.1073/pnas.1900176116

PMCID: PMC6613185 [Available on 2019-12-19]

PMID: 31217290

Conflict of interest statement: The authors declare no conflict of interest.

10. Biomaterials. 2019 Sep;216:119253. doi: 10.1016/j.biomaterials.2019.119253. Epub

2019 Jun 6.

A sandwich-type electrochemical aptasensor for Mycobacterium tuberculosis MPT64

antigen detection using C60NPs decorated N-CNTs/GO nanocomposite coupled with

conductive PEI-functionalized metal-organic framework.

Chen Y(1), Liu X(2), Guo S(2), Cao J(3), Zhou J(4), Zuo J(4), Bai L(5).

Author information:

(1)Department of Respiratory and Critical Care Medicine, The First Affiliated

Hospital of Chongqing Medical University, Chongqing, 400016, PR China;

Engineering Technology Research Center for Pharmacodynamic Evaluation of

Chongqing, College of Pharmacy, Chongqing Medical University, Chongqing, 400016,

PR China.

(2)Department of Respiratory and Critical Care Medicine, The First Affiliated

Hospital of Chongqing Medical University, Chongqing, 400016, PR China.

(3)Department of Respiratory and Critical Care Medicine, West China Hospital of

Sichuan University, Chengdu, 610041, PR China.

...

The present work described a novel sandwich-type electrochemical aptasensor for

rapid and sensitive determination of Mycobacterium tuberculosis MPT64 antigen.

Herein, a novel carbon nanocomposite composed of fullerene nanoparticles,

nitrogen-doped carbon nanotubes and graphene oxide (C60NPs-N-CNTs/GO) was

facilely synthesized for the first time, which not only possessed a large

specific surface area and excellent conductivity, but also exhibited outstanding

inherent electroactive property, and therefore served as nanocarrier and redox

nanoprobe simultaneously. Gold nanoparticles (AuNPs) was then uniformly anchored

onto the surface of such nanocomposite via Au-N bonds to bind with MPT64 antigen

aptamer Ⅱ (MAA Ⅱ), forming the tracer label to realize generation and

amplification of electrochemical signal. Additionally, conductive

polyethyleneimine (PEI)-functionalized Fe-based metal-organic framework (P-MOF)

was used as a sensing platform to absorb bimetallic core-shell Au-Pt

nanoparticles (Au@Pt), which could accelerate electron transfer and increase the

immobilization of MPT64 antigen aptamer Ⅰ (MAA Ⅰ). After the typical

sandwich-type protein-aptamer recognition, the inherent electroactivity of the

tracer label was provoked by tetraoctylammonium bromide (TOAB), leading to a

well-defined current response. Under the optimum condition, the proposed

aptasensor showed a wide linear range for MPT64 detection from 1?fg/mL to 1?ng/mL

with a limit of detection (LOD) as low as 0.33?fg/mL. More importantly, it was

successfully used for MPT64 antigen detection in human serum, exhibiting a

promising prospect for TB diagnosis in clinical practice.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.biomaterials.2019.119253

PMID: 31202103

11. Clin Infect Dis. 2019 Jun 12. pii: ciz502. doi: 10.1093/cid/ciz502. [Epub ahead

of print]

TB Preventive Therapy for individuals exposed to drug-resistant tuberculosis:

feasibility and safety of a community-based delivery of

fluoroquinolone-containing preventive regimen.

Malik AA(1)(2)(3), Fuad J(1), Siddiqui S(1), Amanullah F(1)(2), Jaswal M(1),

Pmdcp ZB(1), Jabeen F(1), Fatima R(4), Yuen CM(5)(6), Salahuddin N(1)(7), Khan

AJ(1)(2), Keshavjee S(5)(6)(8), Becerra MC(5)(6)(8), Hussain H(2).

Author information:

(1)Global Health Directorate, Indus Health Network, Karachi, Pakistan.

(2)Interactive Research and Development (IRD) Global, Singapore.

(3)Emory University Rollins School of Public Health, Atlanta, GA, USA.

...

BACKGROUND: Observational studies have demonstrated the effectiveness of a

fluoroquinolone-based regimen to treat individuals exposed to or presumed to be

infected with drug-resistant (DR)-TB. We sought to assess the feasibility of this

approach in an urban setting in South Asia.

METHODS: From February 2016 until March 2017, all household contacts of DR-TB

patients enrolled at The Indus Hospital were screened for TB symptoms at home.

Children 0-17 years, symptomatic adults and those with an immunocompromising

condition (HIV, diabetes or malnutrition) were evaluated for TB disease. Contacts

diagnosed with TB disease were started on treatment. Contacts without TB disease

(i) younger than 5 years; (ii) between 5 and 17 years old with either a positive

TST or an immunocompromising condition; or (iii) 18 years and older with an

immunocompromising conditionwere offered six month treatment with a

fluoroquinolone.

RESULTS: One hundred households with 800 contacts were enrolled: 353 (44·1%)

individuals age 17 years or younger with a median age of 19 years (IQR: 10-32);

423 (52·9%) were males. In total, 737 (92·1%) individuals were screened, of which

eight were already on treatment for TB (1·1%), and another three (0·4%) contacts

were diagnosed with TB disease and started on treatment. Of 215 eligible for

infection treatment, 172 (80·0%) contacts initiated and 121 (70·3%) completed

treatment. No TB disease nor significant adverse events were observed during 12

months of follow up in any group.

CONCLUSIONS: Fluoroquinolone-based treatment for contacts with presumed DR-TB

infection is feasible and well tolerated in a high TB burden setting.

© The Author(s) 2019. Published by Oxford University Press for the Infectious

Diseases Society of America. All rights reserved. For permissions, e-mail:

journals.permissions@oup.com.

DOI: 10.1093/cid/ciz502

PMID: 31190072

12. Clin J Am Soc Nephrol. 2019 Jul 5;14(7):1002-1010. doi: 10.2215/CJN.14471218.

Epub 2019 Jun 6.

Association of CKD with Incident Tuberculosis.

Park S(1)(2), Lee S(2)(3), Kim Y(2)(4), Lee Y(2)(3), Kang MW(2)(3), Cho S(2), Han

K(5), Han SS(2)(6), Lee H(2)(6), Lee JP(3)(6)(7), Joo KW(2)(3)(6), Lim

CS(3)(6)(7), Kim YS(1)(2)(3)(6), Kim DK(8)(3)(6).

Author information:

(1)Departments of Biomedical Sciences and.

(2)Department of Internal Medicine, Seoul National University Hospital, Seoul,

Korea.

(3)Internal Medicine and.

...

BACKGROUND AND OBJECTIVES: The incidence and risk of Mycobacterium tuberculosis

in people with predialysis CKD has rarely been studied, although CKD prevalence

is increasing in certain countries where Mycobacterium tuberculosis is endemic.

We aimed to investigate the association between predialysis CKD and active

Mycobacterium tuberculosis risks in a nation with moderate Mycobacterium

tuberculosis risk.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this nationwide retrospective

cohort study, we reviewed the National Health Insurance Database of Korea,

screening 17,020,339 people who received a national health screening two or more

times from 2012 to 2016. Predialysis CKD was identified with consecutive

laboratory results indicative of CKD (e.g., persistent eGFR <60 ml/min per 1.73

m2 or dipstick albuminuria). People with preexisting active Mycobacterium

tuberculosis or kidney replacement therapy were excluded. A 1:1 matched control

group without CKD was included with matching for age, sex, low-income status, and

smoking history. The risk of incident active Mycobacterium tuberculosis,

identified in the claims database, was assessed by the multivariable Cox

regression model, which included both matched and unmatched variables (e.g., body

mass index, diabetes, hypertension, places of residence, and other

comorbidities).

RESULTS: We included 408,873 people with predialysis CKD and the same number of

controls. We identified 1704 patients with active Mycobacterium tuberculosis

(incidence rate =137.5/100,000 person-years) in the predialysis CKD group and

1518 patients with active Mycobacterium tuberculosis (incidence rate

=121.9/100,000 person-years) in the matched controls. The active Mycobacterium

tuberculosis risk was significantly higher in the predialysis CKD group (adjusted

hazard ratio, 1.21; 95% confidence interval, 1.13 to 1.30). The risk factors for

active Mycobacterium tuberculosis among the predialysis CKD group were old age,

men, current smoking, low income, underlying diabetes, chronic obstructive

pulmonary disease, and Kidney Disease Improving Global Outcomes CKD stage 1

(eGFR≥90 ml/min per 1.73 m2 with persistent albuminuria) or stage 4/5 without

dialysis (eGFR<30 ml/min per 1.73 m2).

CONCLUSIONS: In the Korean population, the incidence of active Mycobacterium

tuberculosis was higher in people with versus without predialysis CKD.

Copyright © 2019 by the American Society of Nephrology.

DOI: 10.2215/CJN.14471218

PMCID: PMC6625615 [Available on 2020-07-05]

PMID: 31171591

13. J Infect Dis. 2019 Jun 4. pii: jiz285. doi: 10.1093/infdis/jiz285. [Epub ahead of print]

Non-tuberculous Mycobacteria and Heterologous Immunity to Tuberculosis.

Shah JA(1)(2), Lindestam Arlehamn CS(3), Horne DJ(1), Sette A(3)(4), Hawn TR(1).

Author information:

(1)Tuberculosis Research and Training Center, Department of Medicine, University

of Washington, Seattle, WA.

(2)VA Puget Sound Health Care System, Seattle, WA.

(3)Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla,

CA.

(4)University of California San Diego, La Jolla, CA.

Development of an improved tuberculosis (TB) vaccine is a high worldwide public

health priority. Bacillus Calmette-Guerin (BCG), the only licensed TB vaccine,

provides variable efficacy against adult pulmonary TB, but why this protection

varies is unclear. Humans are regularly exposed to non-tuberculous mycobacteria

(NTM) that live in soil and water reservoirs and vary in different geographic

regions around the world. Immunologic cross-reactivity across mycobacterial

species and tissue compartment-specific immune responses may explain disparate

outcomes of BCG vaccination, as well as susceptibility to Mycobacterium

tuberculosis (Mtb) infection and TB disease. Evidence supporting this hypothesis

is increasing, although it has not been rigorously tested due to a lack of

reliable tools to measure NTM-specific immune responses. Conserved

pathogen-associated molecular pattern molecules (PAMPs) among Mycobacteria may

activate similar innate immune pathways and conserved antigens may induce

heterologous T-cell responses during NTM infection that modulate immunity to TB

and BCG. In this review, we describe the progress and bottlenecks in research on

NTM epidemiology, immunology and heterologous immunity to Mtb. With ongoing

efforts to develop new vaccines for TB, understanding the effect of NTM on

vaccine efficacy may be a critical determinant of success.

© The Author(s) 2019. Published by Oxford University Press for the Infectious

Diseases Society of America. All rights reserved. For permissions, e-mail:

journals.permissions@oup.com.

DOI: 10.1093/infdis/jiz285

PMID: 31165861

14. Eur Respir J. 2019 Jun 27;53(6). pii: 1802302. doi: 10.1183/13993003.02302-2018.

Print 2019 Jun.

Detection, survival and infectious potential of Mycobacterium tuberculosis in the

environment: a review of the evidence and epidemiological implications.

Martinez L(1), Verma R(2), Croda J(3)(4), Horsburgh CR Jr(5)(6), Walter KS(2),

Degner N(2), Middelkoop K(7)(8), Koch A(9), Hermans S(7)(10), Warner DF(9)(11),

Wood R(7), Cobelens F(10), Andrews JR(2).

Author information:

(1)Division of Infectious Diseases and Geographic Medicine, School of Medicine,

Stanford University, Stanford, CA, USA leomarti@stanford.edu.

(2)Division of Infectious Diseases and Geographic Medicine, School of Medicine,

Stanford University, Stanford, CA, USA.

(3)Oswaldo Cruz Foundation, Campo Grande and Salvador, Brazil.

...

Much remains unknown about Mycobacterium tuberculosis transmission. Seminal

experimental studies from the 1950s demonstrated that airborne expulsion of

droplet nuclei from an infectious tuberculosis (TB) patient is the primary route

of transmission. However, these findings did not rule out other routes of M.

tuberculosis transmission. We reviewed historical scientific evidence from the

late 19th/early 20th century and contemporary studies investigating the presence,

persistence and infectiousness of environmental M. tuberculosis We found both

experimental and epidemiological evidence supporting the presence and viability

of M. tuberculosis in multiple natural and built environments for months to

years, presumably following contamination by a human source. Furthermore, several

studies confirm M. tuberculosis viability and virulence in the environment using

guinea pig and mouse models. Most of this evidence was historical; however,

several recent studies have reported consistent findings of M. tuberculosis

detection and viability in the environment using modern methods. Whether M.

tuberculosis in environments represents an infectious threat to humans requires

further investigation; this may represent an untapped source of data with which

to further understand M. tuberculosis transmission. We discuss potential

opportunities for harnessing these data to generate new insights into TB

transmission in congregate settings.

Copyright ©ERS 2019.

DOI: 10.1183/13993003.02302-2018

PMID: 31048345

15. J Infect Dis. 2019 Jun 19;220(2):316-320. doi: 10.1093/infdis/jiz104.

Cryptic Resistance Mutations Associated With Misdiagnoses of Multidrug-Resistant

Tuberculosis.

Cancino-Muñoz I(1)(2), Moreno-Molina M(1), Furió V(1), Goig GA(1), Torres-Puente

M(1), Chiner-Oms Á(3), Villamayor LM(2), Sanz F(4), Guna-Serrano MR(5), Comas

I(1)(6).

Author information:

(1)Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones

Científicas.

(2)Genomics and Health Unit, FISABIO Public Health, Consorci Hospital General

Universitari de València, Valencia, Spain.

(3)Unidad Mixta "Infección y Salud Pública," Fundación para el Fomento de la

Investigación Sanitaria y Biomédica de la Comunitat Valenciana

(FISABIO)-Conselleria de Sanitat Universal i Salut Pública.

...

Understanding why some multidrug-resistant tuberculosis cases are not detected by

rapid phenotypic and genotypic routine clinical tests is essential to improve

diagnostic assays and advance toward personalized tuberculosis treatment. Here,

we combine whole-genome sequencing with single-colony phenotyping to identify a

multidrug-resistant strain that had infected a patient for 9 years. Our

investigation revealed the failure of rapid testing and genome-based prediction

tools to identify the multidrug-resistant strain. The false-negative findings

were caused by uncommon rifampicin and isoniazid resistance mutations. Although

whole-genome sequencing data helped to personalize treatment, the patient

developed extensively drug-resistant tuberculosis, highlighting the importance of

coupling new diagnostic methods with appropriate treatment regimens.

© The Author(s) 2019. Published by Oxford University Press for the Infectious

Diseases Society of America.

DOI: 10.1093/infdis/jiz104

PMCID: PMC6581888

PMID: 30875421

16. J Antimicrob Chemother. 2019 Jun 1;74(6):1477-1483. doi: 10.1093/jac/dkz048.

Rifampicin and rifabutin resistance in 1003 Mycobacterium tuberculosis clinical

isolates.

Farhat MR(1)(2), Sixsmith J(3), Calderon R(4), Hicks ND(3), Fortune SM(3), Murray

M(5)(6).

Author information:

(1)Department of Biomedical Informatics, Harvard Medical School, 10 Shattuck

Street, Boston, MA, USA.

(2)Division of Pulmonary and Critical Care, Massachusetts General Hospital, 55

Fruit Street, Boston, MA, USA.

(3)Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of

Public Health, 677 Huntington Avenue, Boston, MA, USA.

...

OBJECTIVES: Drug-resistant TB remains a public health challenge. Rifamycins are

among the most potent anti-TB drugs. They are known to target the RpoB subunit of

RNA polymerase; however, our understanding of how rifamycin resistance is

genetically encoded remains incomplete. Here we investigated rpoB genetic

diversity and cross-resistance between the two rifamycin drugs rifampicin and

rifabutin.

METHODS: We performed WGS of 1003 Mycobacterium tuberculosis clinical isolates

and determined MICs of both rifamycin agents on 7H10 agar using the indirect

proportion method. We generated rpoB mutants in a laboratory strain and measured

their antibiotic susceptibility using the alamarBlue reduction assay.

RESULTS: Of the 1003 isolates, 766 were rifampicin resistant and 210 (27%) of

these were rifabutin susceptible; 102/210 isolates had the rpoB mutation D435V

(Escherichia coli D516V). Isolates with discordant resistance were 17.2 times

more likely to harbour a D435V mutation than those resistant to both agents (OR

17.2, 95% CI 10.5-27.9, P value <10-40). Compared with WT, the D435V in vitro

mutant had an increased IC50 of both rifamycins; however, in both cases to a

lesser degree than the S450L (E. coli S531L) mutation.

CONCLUSIONS: The observation that the rpoB D435V mutation produces an increase in

the IC50 of both drugs contrasts with findings from previous smaller studies that

suggested that isolates with the D435V mutation remain rifabutin susceptible

despite being rifampicin resistant. Our finding thus suggests that the

recommended critical testing concentration for rifabutin should be revised.

© The Author(s) 2019. Published by Oxford University Press on behalf of the

British Society for Antimicrobial Chemotherapy. All rights reserved. For

permissions, please email: journals.permissions@oup.com.

DOI: 10.1093/jac/dkz048

PMCID: PMC6524487 [Available on 2020-02-21]

PMID: 30793747

17. J Antimicrob Chemother. 2019 Jun 1;74(6):1627-1633. doi: 10.1093/jac/dkz052.

Bedaquiline kills persistent Mycobacterium tuberculosis with no disease relapse:

an in vivo model of a potential cure.

Hu Y(1), Pertinez H(2), Liu Y(1), Davies G(2), Coates A(1).

Author information:

(1)Institute for Infection and Immunity, St George's, University of London,

Cranmer Terrace, London SW17 ORE, UK.

(2)Department of Molecular and Clinical Pharmacology, University of Liverpool,

Liverpool L69 3GF, UK.

OBJECTIVES: Non-replicating persistent Mycobacterium tuberculosis is difficult to

kill since the organisms become undetectable using our conventional diagnostic

methods and tolerant to anti-TB drugs. Resuscitation-promoting factors (RPFs)

have been used to 'wake up' non-replicating persisters, making them easy to

detect. Bedaquiline is a novel bactericidal and sterilizing anti-TB drug with the

potential to eradicate RPF-dependent persistent M. tuberculosis. We present the

first head-to-head comparison between the standard anti-TB regimen and a

bedaquiline-modified regimen in eradicating RPF-dependent persistent M.

tuberculosis, using the well-defined Cornell Model.

METHODS: M. tuberculosis-infected mice were treated for 14 weeks with either the

standard regimen (rifampicin, isoniazid, pyrazinamide and ethambutol) or the same

regimen where ethambutol was replaced by bedaquiline. The efficacy of both drug

regimens was measured by cfu count elimination and eradication of persistent

bacteria, which was evaluated using culture filtrate (CF) containing RPFs. At the

end of treatment, the remaining cfu count-negative mice were administered

hydrocortisone for 8 weeks. The induced disease relapse rates were determined by

the percentage of mice that became positive for M. tuberculosis in the lung,

spleen or both.

RESULTS: The bedaquiline-containing regimen achieved total organ cfu count

clearance at 8 weeks after treatment initiation, faster than the standard regimen

(14 weeks). Importantly, the bedaquiline-containing regimen removed CF-dependent

persistent bacilli at 8 weeks, leading to no disease relapse.

CONCLUSIONS: A bedaquiline regimen eradicated persistent TB infections and

completely prevented disease relapse in mice. These findings offer the potential

for a faster cure for TB, with reduced relapse rate.

© The Author(s) 2019. Published by Oxford University Press on behalf of the

British Society for Antimicrobial Chemotherapy. All rights reserved. For

permissions, please email: journals.permissions@oup.com.

DOI: 10.1093/jac/dkz052

PMID: 30789209

18. Clin Pharmacokinet. 2019 Jun;58(6):815-826. doi: 10.1007/s40262-018-00732-2.

Personalized Tuberculosis Treatment Through Model-Informed Dosing of Rifampicin.

van Beek SW(1), Ter Heine R(1), Keizer RJ(2), Magis-Escurra C(3), Aarnoutse

RE(1), Svensson EM(4)(5).

Author information:

(1)Department of Pharmacy, Radboud Institute for Health Sciences, Radboud

University Medical Center, Nijmegen, The Netherlands.

(2)InsightRX, San Francisco, CA, USA.

(3)Department of Respiratory Diseases, Radboud University Medical

Center-Dekkerswald, Groesbeek, The Netherlands.

...

BACKGROUND AND OBJECTIVE: This study proposes a model-informed approach for

therapeutic drug monitoring (TDM) of rifampicin to improve tuberculosis (TB)

treatment.

METHODS: Two datasets from pulmonary TB patients were used: a pharmacokinetic

study (34 patients, 373 samples), and TDM data (96 patients, 391 samples)

collected at Radboud University Medical Center, The Netherlands. Nine suitable

population pharmacokinetic models of rifampicin were identified in the literature

and evaluated on the datasets. A model developed by Svensson et al. was found to

be the most suitable based on graphical goodness of fit, residual diagnostics,

and predictive performance. Prediction of individual area under the

concentration-time curve from time zero to 24 h (AUC24) and maximum concentration

(Cmax) employing various sampling strategies was compared with a previously

established linear regression TDM strategy, using sampling at 2, 4, and 6 h, in

terms of bias and precision (mean error [ME] and root mean square error [RMSE]).

RESULTS: A sampling strategy using 2- and 4-h blood collection was selected to be

the most suitable. The bias and precision of the two strategies were comparable,

except that the linear regression strategy was more biased in prediction of the

AUC24 than the model-informed approach (ME of 9.9% and 1.5%, respectively). A

comparison of resulting dose advice, using predictions on a simulated dataset,

showed no significant difference in sensitivity or specificity between the two

methods. The model was successfully implemented in the InsightRX precision dosing

platform.

CONCLUSION: Blood sampling at 2 and 4 h, combined with model-based prediction,

can be used instead of the currently used linear regression strategy, shortening

the sampling by 2 h and one sampling point without performance loss while

simultaneously offering flexibility in sampling times.

DOI: 10.1007/s40262-018-00732-2

PMID: 30671890