2019年
No.13
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 [Indexed for MEDLINE]
2. Acc Chem Res. 2019 Aug 20;52(8):2340-2348. doi: 10.1021/acs.accounts.9b00275.
Epub 2019 Jul 30.
Harnessing Biological Insight to Accelerate Tuberculosis Drug Discovery.
de Wet TJ(1)(2), Warner DF(1)(3), Mizrahi V(1)(3).
Author information:
(1)SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit and DST/NRF Centre of
Excellence for Biomedical TB Research, Department of Pathology and Institute of
Infectious Disease and Molecular Medicine , University of Cape Town ,
Observatory, Cape Town 7925 , South Africa.
(2)Department of Integrative Biomedical Sciences , University of Cape Town ,
Observatory, Cape Town 7925 , South Africa.
(3)Wellcome Centre for Infectious Disease Research in Africa , University of Cape
Town , Observatory, Cape Town 7925 , South Africa.
Tuberculosis (TB) is the leading cause of mortality globally resulting from an
infectious disease, killing almost 1.6 million people annually and accounting for
approximately 30% of deaths attributed to antimicrobial resistance (AMR). This
despite the widespread administration of a neonatal vaccine, and the availability
of an effective combination drug therapy against the causative agent,
Mycobacterium tuberculosis (Mtb). Instead, TB prevalence worldwide is
characterized by high-burden regions in which co-epidemics, such as HIV, and
social and economic factors, undermine efforts to control TB. These elements
additionally ensure conditions that favor the emergence of drug-resistant Mtb
strains, which further threaten prospects for future TB control. To address this
challenge, significant resources have been invested in developing a TB drug
pipeline, an initiative given impetus by the recent regulatory approval of two
new anti-TB drugs. However, both drugs have been reserved for drug-resistant
disease, and the seeming inevitability of new resistance plus the recognized need
to shorten the duration of chemotherapy demands continual replenishment of the
pipeline with high-quality "hits" with novel mechanisms of action. This
represents a massive challenge, which has been undermined by key gaps in our
understanding of Mtb physiology and metabolism, especially during host infection.
Whereas drug discovery for other bacterial infections can rely on predictive in
vitro assays and animal models, for Mtb, inherent metabolic flexibility and
uncertainties about the nutrients available to infecting bacilli in different
host (micro)environments instead requires educated predictions or demonstrations
of efficacy in animal models of arguable relevance to human disease. Even
microbiological methods for enumeration of viable mycobacterial cells are fraught
with complication. Our research has focused on elucidating those aspects of
mycobacterial metabolism that contribute to the robustness of the bacillus to
host immunological defenses and applied antibiotics and that, possibly, drive the
emergence of drug resistance. This work has identified a handful of metabolic
pathways that appear vulnerable to antibiotic targeting. Those highlighted, here,
include the inter-related functions of pantothenate and coenzyme A biosynthesis
and recycling and nucleotide metabolism-the last of which reinforces our view
that DNA metabolism constitutes an under-explored area for new TB drug
development. Although nonessential functions have traditionally been
deprioritized for antibiotic development, a common theme emerging from this work
is that these very functions might represent attractive targets because of the
potential to cripple mechanisms critical to bacillary survival under stress (for
example, the RelMtb-dependent stringent response) or to adaptability under
unfavorable, potentially lethal, conditions including antibiotic therapy (for
example, DnaE2-dependent SOS mutagenesis). The bar, however, is high:
demonstrating convincingly the likely efficacy of this strategy will require
innovative models of human TB disease. In the concluding section, we focus on the
need for improved techniques to elucidate mycobacterial metabolism during
infection and its impact on disease outcomes. Here, we argue that developments in
other fields suggest the potential to break through this barrier by harnessing
chemical-biology approaches in tandem with the most advanced technologies. As
researchers based in a high-burden country, we are impelled to continue
participating in this important endeavor.
DOI: 10.1021/acs.accounts.9b00275
PMCID: PMC6704484
PMID: 31361123
3. Nat Med. 2019 Jul;25(7):1175. doi: 10.1038/s41591-019-0519-y.
Publisher Correction: IFN-γ-independent immune markers of Mycobacterium
tuberculosis exposure.
Lu LL(1)(2), Smith MT(3), Yu KKQ(3), Luedemann C(2), Suscovich TJ(2), Grace
PS(2), Cain A(2), Yu WH(2)(4), McKitrick TR(5), Lauffenburger D(4), Cummings
RD(5), Mayanja-Kizza H(6), Hawn TR(3), Boom WH(7), Stein CM(7)(8), Fortune
SM(1)(2), Seshadri C(9), Alter G(10).
Author information:
(1)Department of Immunology and Infectious Diseases, Harvard TH Chan School of
Public Health, Boston, MA, USA.
(2)Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
(3)Department of Medicine, University of Washington, Seattle, WA, USA.
…
Erratum for
Nat Med. 2019 Jun;25(6):977-987.
In the version of this article originally published, there was an error in the
abstract. The word disease should not have been included in the sentence "These
individuals were highly exposed to Mtb but tested negative disease by IFN-γ
release assay and tuberculin skin test, 'resisting' development of classic LTBI".
The sentence should have been "These individuals were highly exposed to Mtb but
tested negative by IFN-γ release assay and tuberculin skin test, 'resisting'
development of classic LTBI." The error has been corrected in the HTML and PDF
versions of this article.
DOI: 10.1038/s41591-019-0519-y
PMID: 31222179
4. Proc Natl Acad Sci U S A. 2019 Aug 13;116(33):16326-16331. doi:
10.1073/pnas.1820683116. Epub 2019 Jul 31.
Phase separation and clustering of an ABC transporter in Mycobacterium
tuberculosis.
Heinkel F(1)(2), Abraham L(3), Ko M(4), Chao J(3)(4), Bach H(4), Hui LT(2), Li
H(1)(2), Zhu M(1)(2), Ling YM(2), Rogalski JC(1), Scurll J(5), Bui JM(1)(2),
Mayor T(1)(2), Gold MR(3), Chou KC(6), Av-Gay Y(3)(4), McIntosh LP(7)(2)(6),
Gsponer J(7)(2).
Author information:
(1)Michael Smith Laboratories, University of British Columbia, Vancouver, BC,
Canada V6T 1Z4.
(2)Department of Biochemistry and Molecular Biology, University of British
Columbia, Vancouver, BC, Canada V6T 1Z3.
(3)Department of Microbiology and Immunology, University of British Columbia,
Vancouver, BC, Canada V6T 1Z3.
…
Phase separation drives numerous cellular processes, ranging from the formation
of membrane-less organelles to the cooperative assembly of signaling proteins.
Features such as multivalency and intrinsic disorder that enable condensate
formation are found not only in cytosolic and nuclear proteins, but also in
membrane-associated proteins. The ABC transporter Rv1747, which is important for
Mycobacterium tuberculosis (Mtb) growth in infected hosts, has a cytoplasmic
regulatory module consisting of 2 phosphothreonine-binding Forkhead-associated
domains joined by an intrinsically disordered linker with multiple
phospho-acceptor threonines. Here we demonstrate that the regulatory modules of
Rv1747 and its homolog in Mycobacterium smegmatis form liquid-like condensates as
a function of concentration and phosphorylation. The serine/threonine kinases and
sole phosphatase of Mtb tune phosphorylation-enhanced phase separation and
differentially colocalize with the resulting condensates. The Rv1747 regulatory
module also phase-separates on supported lipid bilayers and forms dynamic foci
when expressed heterologously in live yeast and M. smegmatis cells. Consistent
with these observations, single-molecule localization microscopy reveals that the
endogenous Mtb transporter forms higher-order clusters within the Mycobacterium
membrane. Collectively, these data suggest a key role for phase separation in the
function of these mycobacterial ABC transporters and their regulation via
intracellular signaling.
DOI: 10.1073/pnas.1820683116
PMCID: PMC6697873 [Available on 2020-01-31]
PMID: 31366629
Conflict of interest statement: The authors declare no conflict of interest.
5. Proc Natl Acad Sci U S A. 2019 Aug 6;116(32):15907-15913. doi:
10.1073/pnas.1906606116. Epub 2019 Jul 18.
An essential bifunctional enzyme in Mycobacterium tuberculosis for itaconate
dissimilation and leucine catabolism.
Wang H(1), Fedorov AA(2), Fedorov EV(2), Hunt DM(1), Rodgers A(1), Douglas HL(1),
Garza-Garcia A(1), Bonanno JB(2), Almo SC(2), de Carvalho LPS(3).
Author information:
(1)Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick
Institute, London NW1 1AT, United Kingdom.
(2)Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY
10461.
(3)Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick
Institute, London NW1 1AT, United Kingdom; luiz.carvalho@crick.ac.uk.
Mycobacterium tuberculosis (Mtb) is the etiological agent of tuberculosis.
One-fourth of the global population is estimated to be infected with Mtb,
accounting for ∼1.3 million deaths in 2017. As part of the immune response to Mtb
infection, macrophages produce metabolites with the purpose of inhibiting or
killing the bacterial cell. Itaconate is an abundant host metabolite thought to
be both an antimicrobial agent and a modulator of the host inflammatory response.
However, the exact mode of action of itaconate remains unclear. Here, we show
that Mtb has an itaconate dissimilation pathway and that the last enzyme in this
pathway, Rv2498c, also participates in l-leucine catabolism. Our results from
phylogenetic analysis, in vitro enzymatic assays, X-ray crystallography, and in
vivo Mtb experiments, identified Mtb Rv2498c as a bifunctional β-hydroxyacyl-CoA
lyase and that deletion of the rv2498c gene from the Mtb genome resulted in
attenuation in a mouse infection model. Altogether, this report describes an
itaconate resistance mechanism in Mtb and an l-leucine catabolic pathway that
proceeds via an unprecedented (R)-3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)
stereospecific route in nature.
Copyright © 2019 the Author(s). Published by PNAS.
DOI: 10.1073/pnas.1906606116
PMCID: PMC6689899
PMID: 31320588
Conflict of interest statement: The authors declare no conflict of interest.
6. Free Radic Biol Med. 2019 Jul 15;143:232-239. doi:
10.1016/j.freeradbiomed.2019.07.012. [Epub ahead of print]
Molecular mechanism for the activation of the anti-tuberculosis drug isoniazid by
Mn(III): First detection and unequivocal identification of the critical
N-centered isoniazidyl radical and its exact location.
Qin L(1), Huang CH(1), Xu D(1), Xie LN(2), Shao J(1), Mao L(1), Kalyanaraman
B(3), Zhu BZ(4).
Author information:
(1)State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research
Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing,
100085, P. R. China; University of Chinese Academy of Sciences, Beijing, 100049,
P. R. China.
(2)State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research
Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing,
100085, P. R. China; National Institute of Environmental Health, Chinese Center
for Disease Control and Prevention, Beijing, 100021, China.
(3)Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, 53226,
USA.
(4)State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research
Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing,
100085, P. R. China; University of Chinese Academy of Sciences, Beijing, 100049,
P. R. China; Linus Pauling Institute, Oregon State University, Corvallis, OR,
97331, USA. Electronic address: bzhu@rcees.ac.cn.
Isoniazid (INH), the most-widely used anti-tuberculosis drug, has been shown to
be activated by Mn(III) to produce the reactive carbon-centered isonicotinic acyl
radical, which was considered to be responsible for its anti-tuberculosis
activity. However, it is still not clear whether the previously-proposed
N-centered isoniazidyl radical intermediate can be initially produced or not; and
if so, what is its exact location on the hydrazine group, distal- or
proximal-nitrogen? Through complementary applications of ESR spin-trapping and
HPLC/MS methods, here we show that the characteristic and transient N-centered
isoniazidyl radical intermediate can be detected and identified from INH
activation uniquely by Mn(III)Acetate not by Mn(III) pyrophosphate. The exact
location of the radical was found to be at the distal-nitrogen of the hydrazine
group by 15N-isotope-labeling techniques via using 15N-labeled INH.
Diisonicotinyl hydrazine was identified as a new reaction product from
INH/Mn(III). Analogous results were observed with other hydrazides. This study
represents the first detection and unequivocal identification of the initial
N-centered isoniazidyl radical and its exact location. These findings should
provide a new perspective on the molecular mechanism of INH activation, which may
have broad biomedical and toxicological significance for future research for more
efficient hydrazide anti-tuberculosis drugs.
Copyright © 2019. Published by Elsevier Inc.
DOI: 10.1016/j.freeradbiomed.2019.07.012
PMID: 31319159
7. J Antimicrob Chemother. 2019 Jul 1;74(7):1795-1798. doi: 10.1093/jac/dkz150.
Characterization of linezolid-resistance-associated mutations in Mycobacterium
tuberculosis through WGS.
Pi R(1)(2), Liu Q(1)(2), Jiang Q(1)(2), Gao Q(1)(2).
Author information:
(1)Key Laboratory of Medical Molecular Virology of Ministries of Education and
Health, School of Basic Medical Sciences and Shanghai Public Health Clinical
Center, Fudan University, Shanghai, China.
(2)Shenzhen Center for Chronic Disease Control, Shenzhen, China.
OBJECTIVES: Linezolid is becoming an important antibiotic for treating MDR/XDR
TB, but the mutations conferring resistance to linezolid remain inadequately
characterized. Herein, we investigated the linezolid-resistance-associated
mutations on a whole-genome scale through parallel selections of resistant
isolates in vitro.
METHODS: Ten parallel Mycobacterium tuberculosis H37Rv cultures were subjected to
spontaneous mutant selection on 7H11 agar plates containing 2.5 mg/L linezolid.
The linezolid resistance of resulting colonies was confirmed by growth on a
second linezolid plate. WGS was then performed to identify mutations associated
with linezolid resistance.
RESULTS: Of 181 colonies appearing on the initial linezolid plates, 154 were
confirmed to be linezolid resistant. WGS showed that 88.3% (136/154) of these
isolates had a T460C mutation in rplC, resulting in a C154R substitution. The
other 18 isolates harboured a single mutation in the rrl gene, with G2814T and
G2270T mutations accounting for 7.8% (12/154) and 3.9% (6/154), respectively.
CONCLUSIONS: No mutations in novel genes were associated with linezolid
resistance in a whole-genome investigation of 154 linezolid-resistant isolates
selected in vitro. These results emphasize that rrl and rplC genes should be the
major targets for molecular detection of linezolid resistance.
© 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/dkz150
PMID: 31225608
8. Antioxid Redox Signal. 2019 Jul 24. doi: 10.1089/ars.2018.7708. [Epub ahead of print]
Truncated Hemoglobin O Carries an Autokinase Activity and Facilitates Adaptation
of Mycobacterium tuberculosis Under Hypoxia.
Hade MD(1), Sethi D(1), Datta H(1), Singh S(1), Thakur N(1), Chhaya A(2), Dikshit
KL(1)(2).
Author information:
(1)1CSIR-Institute of Microbial Technology, Chandigarh, India.
(2)2Department of Biotechnology, Panjab University, Chandigarh, India.
Aims: Although the human pathogen, Mycobacterium tuberculosis (Mtb), is strictly
aerobic and requires efficient supply of oxygen, it can survive long stretches of
severe hypoxia. The mechanism responsible for this metabolic flexibility is
unknown. We have investigated a novel mechanism by which hemoglobin O (HbO),
operates and supports its host under oxygen stress. Results: We discovered that
the HbO exists in a phospho-bound state in Mtb and remains associated with the
cell membrane under hypoxia. Deoxy-HbO carries an autokinase activity that
disrupts its dimeric assembly into monomer and facilitates its association with
the cell membrane, supporting survival and adaptation of Mtb under low oxygen
conditions. Consistent with these observations, deletion of the glbO gene in
Mycobacterium bovis bacillus Calmette-Guerin, which is identical to the glbO gene
of Mtb, attenuated its survival under hypoxia and complementation of the glbO
gene of Mtb rescued this inhibition, but phosphorylation-deficient mutant did
not. These results demonstrated that autokinase activity of the HbO modulates its
physiological function and plays a vital role in supporting the survival of its
host under hypoxia. Innovation and Conclusion: Our study demonstrates that the
redox-dependent autokinase activity regulates oligomeric state and membrane
association of HbO that generates a reservoir of oxygen in the proximity of
respiratory membranes to sustain viability of Mtb under hypoxia. These results
thus provide a novel insight into the physiological function of the HbO and
demonstrate its pivotal role in supporting the survival and adaptation of Mtb
under hypoxia.
DOI: 10.1089/ars.2018.7708
PMID: 31218881
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. Nucleic Acids Res. 2019 Jul 26;47(13):6685-6698. doi: 10.1093/nar/gkz449.
CarD and RbpA modify the kinetics of initial transcription and slow promoter
escape of the Mycobacterium tuberculosis RNA polymerase.
Jensen D(1), Manzano AR(1), Rammohan J(1), Stallings CL(2), Galburt EA(1).
Author information:
(1)Department of Biochemistry and Molecular Biophysics, Washington University
School of Medicine, St. Louis, MO 63110, USA.
(2)Department of Molecular Microbiology, Washington University School of
Medicine, St. Louis, MO 63110, USA.
The pathogen Mycobacterium tuberculosis (Mtb), the causative agent of
tuberculosis, enacts unique transcriptional regulatory mechanisms when subjected
to host-derived stresses. Initiation of transcription by the Mycobacterial RNA
polymerase (RNAP) has previously been shown to exhibit different open complex
kinetics and stabilities relative to Escherichia coli (Eco) RNAP. However,
transcription initiation rates also depend on the kinetics following open complex
formation such as initial nucleotide incorporation and subsequent promoter
escape. Here, using a real-time fluorescence assay, we present the first in-depth
kinetic analysis of initial transcription and promoter escape for the Mtb RNAP.
We show that in relation to Eco RNAP, Mtb displays slower initial nucleotide
incorporation but faster overall promoter escape kinetics on the Mtb rrnAP3
promoter. Furthermore, in the context of the essential transcription factors CarD
and RbpA, Mtb promoter escape is slowed via differential effects on initially
transcribing complexes. Finally, based on their ability to increase the rate of
open complex formation and decrease the rate of promoter escape, we suggest that
CarD and RbpA are capable of activation or repression depending on the
rate-limiting step of a given promoter's basal initiation kinetics.
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkz449
PMCID: PMC6648326
PMID: 31127308
11. Eur Respir J. 2019 Jul 11;54(1). pii: 1800353. doi: 10.1183/13993003.00353-2018.
Print 2019 Jul.
Analysis of loss to follow-up in 4099 multidrug-resistant pulmonary tuberculosis
patients.
Walker IF(1), Shi O(2)(3), Hicks JP(4), Elsey H(4), Wei X(2), Menzies D(5), Lan
Z(5), Falzon D(6), Migliori GB(7), Pérez-Guzmán C(8)(9), Vargas MH(9)(10),
García-García L(11), Sifuentes Osornio J(12), Ponce-De-León A(13), van der Walt
M(14), Newell JN(4).
Author information:
(1)Nuffield Centre for International Health and Development, University of Leeds,
Leeds, UK i.walker@leeds.ac.uk.
(2)Dalla Lana School of Public Health, University of Toronto, Toronto, ON,
Canada.
(3)Shenzhen Second People's Hospital, Shenzhen University, Shenzhen, China.
…
Loss to follow-up (LFU) of ≥2 consecutive months contributes to the poor levels
of treatment success in multidrug-resistant tuberculosis (MDR-TB) reported by TB
programmes. We explored the timing of when LFU occurs by month of MDR-TB
treatment and identified patient-level risk factors associated with LFU.We
analysed a dataset of individual MDR-TB patient data (4099 patients from 22
countries). We used Kaplan-Meier survival curves to plot time to LFU and a Cox
proportional hazards model to explore the association of potential risk factors
with LFU.Around one-sixth (n=702) of patients were recorded as LFU. Median
(interquartile range) time to LFU was 7 (3-11)?months. The majority of LFU
occurred in the initial phase of treatment (75% in the first 11?months). Major
risk factors associated with LFU were: age 36-50?years (HR 1.3, 95% CI 1.0-1.6;
p=0.04) compared with age 0-25?years, being HIV positive (HR 1.8, 95% CI 1.2-2.7;
p<0.01) compared with HIV negative, on an individualised treatment regimen (HR
0.7, 95% CI 0.6-1.0; p=0.03) compared with a standardised regimen and a recorded
serious adverse event (HR 0.5, 95% CI 0.4-0.6; p<0.01) compared with no serious
adverse event.Both patient- and regimen-related factors were associated with LFU,
which may guide interventions to improve treatment adherence, particularly in the
first 11?months.
Copyright ©ERS 2019.
DOI: 10.1183/13993003.00353-2018
PMID: 31073080
12. Thorax. 2019 Jul;74(7):675-683. doi: 10.1136/thoraxjnl-2018-212529. Epub 2019 Apr29.
Urban airborne particle exposure impairs human lung and blood Mycobacterium
tuberculosis immunity.
Torres M(1), Carranza C(1), Sarkar S(2), Gonzalez Y(1), Osornio Vargas A(3),
Black K(4), Meng Q(2), Quintana-Belmares R(5), Hernandez M(6), Angeles Garcia
JJF(6), Páramo-Figueroa VH(6), Iñiguez-Garcia MA(7), Flores JL(8), Zhang JJ(9),
Gardner CR(10), Ohman-Strickland P(11), Schwander S(12).
Author information:
(1)Department of Microbiology, Instituto Nacional de Enfermedades Respiratorias,
Mexico City, Mexico.
(2)Environmental and Occupational Health, Rutgers School of Public Health New
Brunswick Campus, Piscataway, New Jersey, USA.
(3)Paediatrics, University of Alberta, Edmonton, Alberta, Canada.
…
RATIONALE: Associations between urban (outdoor) airborne particulate matter (PM)
exposure and TB and potential biological mechanisms are poorly explored.
OBJECTIVES: To examine whether in vivo exposure to urban outdoor PM in Mexico
City and in vitro exposure to urban outdoor PM2.5 (< 2.5 µm median aerodynamic
diameter) alters human host immune cell responses to Mycobacterium tuberculosis.
METHODS: Cellular toxicity (flow cytometry, proliferation assay (MTS assay)), M.
tuberculosis and PM2.5 phagocytosis (microscopy), cytokine-producing cells
(Enzyme-linked immune absorbent spot (ELISPOT)), and signalling pathway markers
(western blot) were examined in bronchoalveolar cells (BAC) and peripheral blood
mononuclear cells (PBMC) from healthy, non-smoking, residents of Mexico City
(n=35; 13 female, 22 male). In vivo-acquired PM burden in alveolar macrophages
(AM) was measured by digital image analysis.
MEASUREMENTS AND MAIN RESULTS: In vitro exposure of AM to PM2.5 did not affect M.
tuberculosis phagocytosis. High in vivo-acquired AM PM burden reduced
constitutive, M. tuberculosis and PM-induced interleukin-1β production in freshly
isolated BAC but not in autologous PBMC while it reduced constitutive production
of tumour necrosis factor-alpha in both BAC and PBMC. Further, PM burden was
positively correlated with constitutive, PM, M. tuberculosis and purified protein
derivative (PPD)-induced interferon gamma (IFN-γ) in BAC, and negatively
correlated with PPD-induced IFN-γ in PBMC.
CONCLUSIONS: Inhalation exposure to urban air pollution PM impairs important
components of the protective human lung and systemic immune response against M.
tuberculosis. PM load in AM is correlated with altered M. tuberculosis-induced
cytokine production in the lung and systemic compartments. Chronic PM exposure
with high constitutive expression of proinflammatory cytokines results in
relative cellular unresponsiveness.
© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and
permissions. Published by BMJ.
DOI: 10.1136/thoraxjnl-2018-212529
PMID: 31036772
Conflict of interest statement: Competing interests: None declared.
13. Chemistry. 2019 Jul 2;25(37):8894-8902. doi: 10.1002/chem.201901640. Epub 2019
Jun 6.
Synthesis of New Cyclomarin Derivatives and Their Biological Evaluation towards
Mycobacterium Tuberculosis and Plasmodium Falciparum.
Kiefer A(1), Bader CD(2), Held J(3), Esser A(4), Rybniker J(5), Empting M(6),
Müller R(2)(7), Kazmaier U(1).
Author information:
(1)Organic Chemistry, Saarland University, Campus C4.2, 66123, Saarbrücken,
Germany.
(2)Department Microbial Natural Products (MINS), Helmholtz-Institute for
Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research
(HZI), Campus E8.1, 66123, Saarbrücken, Germany.
(3)Department of Tropical Medicine, University of Tübingen, Wilhelmstraße 27,
72074, Tübingen, Germany.
…
Cyclomarins are highly potent antimycobacterial and antiplasmodial cyclopeptides
isolated from a marine bacterium (Streptomyces sp.). Previous studies have
identified the target proteins and elucidated a novel mode of action, however
there are currently only a few studies examining the structure-activity
relationship (SAR) for both pathogens. Herein, we report the synthesis and
biological evaluation of 17 novel desoxycyclomarin-inspired analogues.
Optimization via side chain modifications of the non-canonical amino acids led to
potent lead structures for each pathogen.
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
DOI: 10.1002/chem.201901640
PMID: 31012978 [Indexed for MEDLINE]
14. Bioinformatics. 2019 Jul 1;35(13):2276-2282. doi: 10.1093/ bioinformatics/ bty949.
Application of machine learning techniques to tuberculosis drug resistance
analysis.
Kouchaki S(1), Yang Y(1), Walker TM(2)(3), Sarah Walker A(2)(3)(4), Wilson DJ(5),
Peto TEA(2)(3), Crook DW(2)(3)(6); CRyPTIC Consortium, Clifton DA(1).
Author information:
(1)Department of Engineering Science, Institute of Biomedical Engineering.
(2)Nuffield Department of Medicine, University of Oxford.
(3)National Institute of Health Research Oxford Biomedical Research Centre, John
Radcliffe Hospital, Oxford, UK.
(4)Medical Research Council Clinical Trials Unit, University College London, UK.
(5)Nuffield Department of Population Health, Big Data Institute, University of
Oxford, Li Ka Shing Centre for Health Information and Discovery, Oxford, UK.
(6)National Infection Service, Public Health England, Colindale, London, UK.
MOTIVATION: Timely identification of Mycobacterium tuberculosis (MTB) resistance
to existing drugs is vital to decrease mortality and prevent the amplification of
existing antibiotic resistance. Machine learning methods have been widely applied
for timely predicting resistance of MTB given a specific drug and identifying
resistance markers. However, they have been not validated on a large cohort of
MTB samples from multi-centers across the world in terms of resistance prediction
and resistance marker identification. Several machine learning classifiers and
linear dimension reduction techniques were developed and compared for a cohort of
13 402 isolates collected from 16 countries across 6 continents and tested 11
drugs.
RESULTS: Compared to conventional molecular diagnostic test, area under curve of
the best machine learning classifier increased for all drugs especially by
23.11%, 15.22% and 10.14% for pyrazinamide, ciprofloxacin and ofloxacin,
respectively (P < 0.01). Logistic regression and gradient tree boosting found to
perform better than other techniques. Moreover, logistic regression/gradient tree
boosting with a sparse principal component analysis/non-negative matrix
factorization step compared with the classifier alone enhanced the best
performance in terms of F1-score by 12.54%, 4.61%, 7.45% and 9.58% for amikacin,
moxifloxacin, ofloxacin and capreomycin, respectively, as well increasing area
under curve for amikacin and capreomycin. Results provided a comprehensive
comparison of various techniques and confirmed the application of machine
learning for better prediction of the large diverse tuberculosis data.
Furthermore, mutation ranking showed the possibility of finding new
resistance/susceptible markers.
AVAILABILITY AND IMPLEMENTATION: The source code can be found at
http://www.robots.ox.ac.uk/ davidc/code.php.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics
online.
© The Author(s) 2018. Published by Oxford University Press.
DOI: 10.1093/bioinformatics/bty949
PMCID: PMC6596891
PMID: 30462147
15. Clin Infect Dis. 2019 Jul 2;69(2):295-305. doi: 10.1093/cid/ciy823.
Plasma Biomarkers to Detect Prevalent or Predict Progressive Tuberculosis
Associated With Human Immunodeficiency Virus-1.
Lesosky M(1)(2), Rangaka MX(2)(3)(4), Pienaar C(1), Coussens AK(2)(5), Goliath
R(2), Mathee S(6), Mwansa-Kambafwile J(2), Maartens G(3), Wilkinson
RJ(2)(3)(7)(8), Wilkinson KA(2)(3)(8).
Author information:
(1)Division of Epidemiology & Biostatistics, School of Public Health and Family
Medicine.
(2)Wellcome Centre for Infectious Diseases Research in Africa, Institute of
Infectious Diseases and Molecular Medicine, Observatory, South Africa.
(3)Department of Medicine, Faculty of Health Sciences, University of Cape Town,
Observatory, South Africa.
…
BACKGROUND: The risk of individuals infected with human immunodeficiency virus
(HIV)-1 developing tuberculosis (TB) is high, while both prognostic and
diagnostic tools remain insensitive. The potential for plasma biomarkers to
predict which HIV-1-infected individuals are likely to progress to active disease
is unknown.
METHODS: Thirteen analytes were measured from QuantiFERON Gold in-tube (QFT)
plasma samples in 421 HIV-1-infected persons recruited within the screening and
enrollment phases of a randomized, controlled trial of isoniazid preventive
therapy. Blood for QFT was obtained pre-randomization. Individuals were
classified into prevalent TB, incident TB, and control groups. Comparisons
between groups, supervised learning methods, and weighted correlation network
analyses were applied utilizing the unstimulated and background-corrected plasma
analyte concentrations.
RESULTS: Unstimulated samples showed higher analyte concentrations in the
prevalent and incident TB groups compared to the control group. The largest
differences were seen for C-X-C motif chemokine 10 (CXCL10), interleukin-2
(IL-2), IL-1α, transforming growth factor-α (TGF-α). A predictive model analysis
using unstimulated analytes discriminated best between the control and prevalent
TB groups (area under the curve [AUC] = 0.9), reasonably well between the
incident and prevalent TB groups (AUC > 0.8), and poorly between the control and
incident TB groups. Unstimulated IL-2 and IFN-γ were ranked at or near the top
for all comparisons, except the comparison between the control vs incident TB
groups. Models using background-adjusted values performed poorly.
CONCLUSIONS: Single plasma biomarkers are unlikely to distinguish between disease
states in HIV-1 co-infected individuals, and combinations of biomarkers are
required. The ability to detect prevalent TB is potentially important, as no
blood test hitherto has been suggested as having the utility to detect prevalent
TB amongst HIV-1 co-infected persons.
© The Author(s) 2018. Published by Oxford University Press for the Infectious
Diseases Society of America.
DOI: 10.1093/cid/ciy823
PMCID: PMC6603269
PMID: 30256919
16. Lancet Infect Dis. 2019 Oct;19(10):1129-1137. doi: 10.1016/ S1473- 3099(19)30309 -3. Epub 2019 Jul 16.
Long-term all-cause mortality in people treated for tuberculosis: a systematic
review and meta-analysis.
Romanowski K(1), Baumann B(2), Basham CA(3), Ahmad Khan F(4), Fox GJ(5), Johnston
JC(6).
Author information:
(1)Provincial TB Services, British Columbia Centre for Disease Control,
Vancouver, BC, Canada.
(2)Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
(3)Provincial TB Services, British Columbia Centre for Disease Control,
Vancouver, BC, Canada; School of Population and Public Health, University of
British Columbia, Vancouver, BC, Canada.
…
BACKGROUND: Accurate estimates of long-term mortality following tuberculosis
treatment are scarce. This systematic review and meta-analysis aimed to estimate
the post-treatment mortality among tuberculosis survivors, and examine
differences in mortality risk by demographic and clinical characteristics.
METHODS: We systematically searched Embase, MEDLINE, and the Cochrane Database of
Systematic Reviews for cohort studies published in English between Jan 1, 1997,
and May 31, 2018. We included research papers that used a cohort study design,
included bacteriological or clinical confirmation of tuberculosis disease for all
participants, and reported, or provided enough data to calculate, mortality
estimates for people with tuberculosis and a valid control group representative
of the general population. We excluded studies that reported duplicate data, had
a study population of fewer than 50 people overall, had a follow-up period
shorter than 12 months after treatment completion, or had a loss to follow-up of
more than 30%. From eligible studies, we extracted standardised mortality ratios
(SMRs), or calculated them when the data were sufficient, by dividing the sum of
the observed deaths by the sum of the expected deaths. For studies that did not
report SMR as their mortality estimate, either mortality hazard ratios or
mortality rate ratios were extracted and pooled with SMRs. Random-effects
meta-analysis was used to obtain pooled SMRs. Between-study heterogeneity was
estimated with I2. This study was prospectively registered in PROSPERO
(CRD42018092592).
FINDINGS: Of the 7283 unique studies identified, data from ten studies, reporting
on 40?781 individuals and 6922 deaths, were included. The pooled SMR for
all-cause mortality among people with tuberculosis, compared with the control
group, was 2·91 (95% CI 2·21-3·84; I2=99%, pheterogeneity<0·0001). When
restricted to people with confirmed treatment completion or cure, the pooled SMR
was 3·76 (95% CI 3·04-4·66; I2=95%). Effect estimates were similar when
stratified by tuberculosis type, sex, age, and country income category. Causes of
mortality were extracted for 4226 deaths that occurred post-treatment, with most
deaths attributable to cardiovascular disease (20% [95% CI 15-26]; I2=92%).
INTERPRETATION: People treated for tuberculosis have significantly increased
mortality following treatment compared with the general population or matched
controls. These findings support the need for further research to understand and
address the biomedical and social factors that affect the long-term prognosis of
this population.
FUNDING: None.
Copyright © 2019 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(19)30309-3
PMID: 31324519
