New 2-Ethylthio-4-methylaminoquinazoline derivatives inhibiting two subunits of cytochrome bc1 in Mycobacterium tuberculosis.

Abstract:

:The emergence of multi-drug (MDR-TB) and extensively-drug resistant tuberculosis (XDR-TB) is a major threat to the global management of tuberculosis (TB) worldwide. New chemical entities are of need to treat drug-resistant TB. In this study, the mode of action of new, potent quinazoline derivatives was investigated against Mycobacterium tuberculosis (M. tb). Four derivatives 11626141, 11626142, 11626252 and 11726148 showed good activity (MIC ranging from 0.02-0.09 μg/mL) and low toxicity (TD50 ≥ 5μg/mL) in vitro against M. tb strain H37Rv and HepG2 cells, respectively. 11626252 was the most selective compound from this series. Quinazoline derivatives were found to target cytochrome bc1 by whole-genome sequencing of mutants selected with 11626142. Two resistant mutants harboured the transversion T943G (Trp312Gly) and the transition G523A (Gly175Ser) in the cytochrome bc1 complex cytochrome b subunit (QcrB). Interestingly, a third mutant QuinR-M1 contained a mutation in the Rieske iron-sulphur protein (QcrA) leading to resistance to quinazoline and other QcrB inhibitors, the first report of cross-resistance involving QcrA. Modelling of both QcrA and QcrB revealed that all three resistance mutations are located in the stigmatellin pocket, as previously observed for other QcrB inhibitors such as Q203, AX-35, and lansoprazole sulfide (LPZs). Further analysis of the mode of action in vitro revealed that 11626252 exposure leads to ATP depletion, a decrease in the oxygen consumption rate and also overexpression of the cytochrome bd oxidase in M. tb. Our findings suggest that quinazoline-derived compounds are a new and attractive chemical entity for M. tb drug development targeting two separate subunits of the cytochrome bc1 complex.

journal_name

PLoS Pathog

journal_title

PLoS pathogens

authors

Lupien A,Foo CS,Savina S,Vocat A,Piton J,Monakhova N,Benjak A,Lamprecht DA,Steyn AJC,Pethe K,Makarov VA,Cole ST

doi

10.1371/journal.ppat.1008270

subject

Has Abstract

pub_date

2020-01-23 00:00:00

pages

e1008270

issue

1

eissn

1553-7366

issn

1553-7374

pii

PPATHOGENS-D-19-01375

journal_volume

16

pub_type

杂志文章
  • Organising the cell cycle in the absence of transcriptional control: Dynamic phosphorylation co-ordinates the Trypanosoma brucei cell cycle post-transcriptionally.

    abstract::The cell division cycle of the unicellular eukaryote Trypanosome brucei is tightly regulated despite the paucity of transcriptional control that results from the arrangement of genes in polycistronic units and lack of dynamically regulated transcription factors. To identify the contribution of dynamic phosphorylation ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1008129

    authors: Benz C,Urbaniak MD

    更新日期:2019-12-12 00:00:00

  • Brucella modulates secretory trafficking via multiple type IV secretion effector proteins.

    abstract::The intracellular pathogenic bacterium Brucella generates a replicative vacuole (rBCV) derived from the endoplasmic reticulum via subversion of the host cell secretory pathway. rBCV biogenesis requires the expression of the Type IV secretion system (T4SS) VirB, which is thought to translocate effector proteins that mo...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1003556

    authors: Myeni S,Child R,Ng TW,Kupko JJ 3rd,Wehrly TD,Porcella SF,Knodler LA,Celli J

    更新日期:2013-01-01 00:00:00

  • Transcriptome-Wide Cleavage Site Mapping on Cellular mRNAs Reveals Features Underlying Sequence-Specific Cleavage by the Viral Ribonuclease SOX.

    abstract::Many viruses express factors that reduce host gene expression through widespread degradation of cellular mRNA. An example of this class of proteins is the mRNA-targeting endoribonuclease SOX from the gamma-herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV). Previous studies indicated that cleavage of messenger...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1005305

    authors: Gaglia MM,Rycroft CH,Glaunsinger BA

    更新日期:2015-12-08 00:00:00

  • Parallel exploitation of diverse host nutrients enhances Salmonella virulence.

    abstract::Pathogen access to host nutrients in infected tissues is fundamental for pathogen growth and virulence, disease progression, and infection control. However, our understanding of this crucial process is still rather limited because of experimental and conceptual challenges. Here, we used proteomics, microbial genetics,...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1003301

    authors: Steeb B,Claudi B,Burton NA,Tienz P,Schmidt A,Farhan H,Mazé A,Bumann D

    更新日期:2013-01-01 00:00:00

  • HIV-1 adaptation studies reveal a novel Env-mediated homeostasis mechanism for evading lethal hypermutation by APOBEC3G.

    abstract::HIV-1 replication normally requires Vif-mediated neutralization of APOBEC3 antiviral enzymes. Viruses lacking Vif succumb to deamination-dependent and -independent restriction processes. Here, HIV-1 adaptation studies were leveraged to ask whether viruses with an irreparable vif deletion could develop resistance to re...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1007010

    authors: Ikeda T,Symeonides M,Albin JS,Li M,Thali M,Harris RS

    更新日期:2018-04-20 00:00:00

  • Evidence that intracellular stages of Leishmania major utilize amino sugars as a major carbon source.

    abstract::Intracellular parasites, such as Leishmania spp, must acquire suitable carbon sources from the host cell in order to replicate. Here we present evidence that intracellular amastigote stages of Leishmania exploit amino sugars in the phagolysosome of mammalian macrophages as a source of carbon and energy. L. major paras...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1001245

    authors: Naderer T,Heng J,McConville MJ

    更新日期:2010-12-23 00:00:00

  • MicroRNA antagonism of the picornaviral life cycle: alternative mechanisms of interference.

    abstract::In addition to modulating the function and stability of cellular mRNAs, microRNAs can profoundly affect the life cycles of viruses bearing sequence complementary targets, a finding recently exploited to ameliorate toxicities of vaccines and oncolytic viruses. To elucidate the mechanisms underlying microRNA-mediated an...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1000820

    authors: Kelly EJ,Hadac EM,Cullen BR,Russell SJ

    更新日期:2010-03-19 00:00:00

  • New Strains Intended for the Production of Inactivated Polio Vaccine at Low-Containment After Eradication.

    abstract::Poliomyelitis has nearly been eradicated through the efforts of the World Health Organization's Global Eradication Initiative raising questions on containment of the virus after it has been eliminated in the wild. Most manufacture of inactivated polio vaccines currently requires the growth of large amounts of highly v...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1005316

    authors: Knowlson S,Burlison J,Giles E,Fox H,Macadam AJ,Minor PD

    更新日期:2015-12-31 00:00:00

  • Species-specific functions of Epstein-Barr virus nuclear antigen 2 (EBNA2) reveal dual roles for initiation and maintenance of B cell immortalization.

    abstract::Epstein-Barr virus (EBV) and related lymphocryptoviruses (LCV) from non-human primates infect B cells, transform their growth to facilitate life-long viral persistence in the host, and contribute to B cell oncogenesis. Co-evolution of LCV with their primate hosts has led to species-specificity so that LCVs preferentia...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1006772

    authors: Mühe J,Wang F

    更新日期:2017-12-20 00:00:00

  • Leishmania mitochondrial peroxiredoxin plays a crucial peroxidase-unrelated role during infection: insight into its novel chaperone activity.

    abstract::Two-cysteine peroxiredoxins are ubiquitous peroxidases that play various functions in cells. In Leishmania and related trypanosomatids, which lack catalase and selenium-glutathione peroxidases, the discovery of this family of enzymes provided the molecular basis for peroxide removal in these organisms. In this report ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1002325

    authors: Castro H,Teixeira F,Romao S,Santos M,Cruz T,Flórido M,Appelberg R,Oliveira P,Ferreira-da-Silva F,Tomás AM

    更新日期:2011-10-01 00:00:00

  • Early primed KLRG1- CMV-specific T cells determine the size of the inflationary T cell pool.

    abstract::Memory T cell inflation is a process in which a subset of cytomegalovirus (CMV) specific CD8 T cells continuously expands mainly during latent infection and establishes a large and stable population of effector memory cells in peripheral tissues. Here we set out to identify in vivo parameters that promote and limit CD...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1007785

    authors: Baumann NS,Welten SPM,Torti N,Pallmer K,Borsa M,Barnstorf I,Oduro JD,Cicin-Sain L,Oxenius A

    更新日期:2019-05-13 00:00:00

  • C. elegans germ cells show temperature and age-dependent expression of Cer1, a Gypsy/Ty3-related retrotransposon.

    abstract::Virus-like particles (VLPs) have not been observed in Caenorhabditis germ cells, although nematode genomes contain low numbers of retrotransposon and retroviral sequences. We used electron microscopy to search for VLPs in various wild strains of Caenorhabditis, and observed very rare candidate VLPs in some strains, in...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1002591

    authors: Dennis S,Sheth U,Feldman JL,English KA,Priess JR

    更新日期:2012-01-01 00:00:00

  • The polyfunctionality of human memory CD8+ T cells elicited by acute and chronic virus infections is not influenced by age.

    abstract::As humans age, they experience a progressive loss of thymic function and a corresponding shift in the makeup of the circulating CD8+ T cell population from naïve to memory phenotype. These alterations are believed to result in impaired CD8+ T cell responses in older individuals; however, evidence that these global cha...

    journal_title:PLoS pathogens

    pub_type: 临床试验,杂志文章

    doi:10.1371/journal.ppat.1003076

    authors: Lelic A,Verschoor CP,Ventresca M,Parsons R,Evelegh C,Bowdish D,Betts MR,Loeb MB,Bramson JL

    更新日期:2012-01-01 00:00:00

  • Timelines of infection and transmission dynamics of H1N1pdm09 in swine.

    abstract::Influenza is a major cause of mortality and morbidity worldwide. Despite numerous studies of the pathogenesis of influenza in humans and animal models the dynamics of infection and transmission in individual hosts remain poorly characterized. In this study, we experimentally modelled transmission using the H1N1pdm09 i...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1008628

    authors: Canini L,Holzer B,Morgan S,Dinie Hemmink J,Clark B,sLoLa Dynamics Consortium.,Woolhouse MEJ,Tchilian E,Charleston B

    更新日期:2020-07-24 00:00:00

  • Immobility in the sedentary plant-parasitic nematode H. glycines is associated with remodeling of neuromuscular tissue.

    abstract::The sedentary plant-parasitic nematodes are considered among the most economically damaging pathogens of plants. Following infection and the establishment of a feeding site, sedentary nematodes become immobile. Loss of mobility is reversed in adult males while females never regain mobility. The structural basis for th...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1007198

    authors: Han Z,Thapa S,Reuter-Carlson U,Reed H,Gates M,Lambert KN,Schroeder NE

    更新日期:2018-08-16 00:00:00

  • Importin β Can Bind Hepatitis B Virus Core Protein and Empty Core-Like Particles and Induce Structural Changes.

    abstract::Hepatitis B virus (HBV) capsids are found in many forms: immature single-stranded RNA-filled cores, single-stranded DNA-filled replication intermediates, mature cores with relaxed circular double-stranded DNA, and empty capsids. A capsid, the protein shell of the core, is a complex of 240 copies of core protein. Matur...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1005802

    authors: Chen C,Wang JC,Pierson EE,Keifer DZ,Delaleau M,Gallucci L,Cazenave C,Kann M,Jarrold MF,Zlotnick A

    更新日期:2016-08-12 00:00:00

  • Competent but complex communication: The phenomena of pheromone-responsive plasmids.

    abstract::Enterococci are robust gram-positive bacteria that are found in a variety of surroundings and that cause a significant number of healthcare-associated infections. The genus possesses a high-efficiency pheromone-responsive plasmid (PRP) transfer system for genetic exchange that allows antimicrobial-resistance determina...

    journal_title:PLoS pathogens

    pub_type: 杂志文章,评审

    doi:10.1371/journal.ppat.1008310

    authors: Sterling AJ,Snelling WJ,Naughton PJ,Ternan NG,Dooley JSG

    更新日期:2020-04-02 00:00:00

  • Structural analysis of HIV-1 maturation using cryo-electron tomography.

    abstract::HIV-1 buds form infected cells in an immature, non-infectious form. Maturation into an infectious virion requires proteolytic cleavage of the Gag polyprotein at five positions, leading to a dramatic change in virus morphology. Immature virions contain an incomplete spherical shell where Gag is arranged with the N-term...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1001215

    authors: de Marco A,Müller B,Glass B,Riches JD,Kräusslich HG,Briggs JA

    更新日期:2010-11-24 00:00:00

  • Bartonella effector protein C mediates actin stress fiber formation via recruitment of GEF-H1 to the plasma membrane.

    abstract::Bartonellae are Gram-negative facultative-intracellular pathogens that use a type-IV-secretion system (T4SS) to translocate a cocktail of Bartonella effector proteins (Beps) into host cells to modulate diverse cellular functions. BepC was initially reported to act in concert with BepF in triggering major actin cytoske...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1008548

    authors: Marlaire S,Dehio C

    更新日期:2021-01-28 00:00:00

  • The impact of serotype-specific vaccination on phylodynamic parameters of Streptococcus pneumoniae and the pneumococcal pan-genome.

    abstract::In the United States, the introduction of the heptavalent pneumococcal conjugate vaccine (PCV) largely eliminated vaccine serotypes (VT); non-vaccine serotypes (NVT) subsequently increased in carriage and disease. Vaccination also disrupts the composition of the pneumococcal pangenome, which includes mobile genetic el...

    journal_title:PLoS pathogens

    pub_type: 杂志文章,随机对照试验

    doi:10.1371/journal.ppat.1006966

    authors: Azarian T,Grant LR,Arnold BJ,Hammitt LL,Reid R,Santosham M,Weatherholtz R,Goklish N,Thompson CM,Bentley SD,O'Brien KL,Hanage WP,Lipsitch M

    更新日期:2018-04-04 00:00:00

  • The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis.

    abstract::The factors that govern the development of tuberculosis disease are incompletely understood. We hypothesized that some strains of Mycobacterium tuberculosis (M. tuberculosis) are more capable of causing disseminated disease than others and may be associated with polymorphisms in host genes responsible for the innate i...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1000034

    authors: Caws M,Thwaites G,Dunstan S,Hawn TR,Lan NT,Thuong NT,Stepniewska K,Huyen MN,Bang ND,Loc TH,Gagneux S,van Soolingen D,Kremer K,van der Sande M,Small P,Anh PT,Chinh NT,Quy HT,Duyen NT,Tho DQ,Hieu NT,Torok E,Hien

    更新日期:2008-03-28 00:00:00

  • Human metapneumovirus Induces Reorganization of the Actin Cytoskeleton for Direct Cell-to-Cell Spread.

    abstract::Paramyxovirus spread generally involves assembly of individual viral particles which then infect target cells. We show that infection of human bronchial airway cells with human metapneumovirus (HMPV), a recently identified paramyxovirus which causes significant respiratory disease, results in formation of intercellula...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1005922

    authors: El Najjar F,Cifuentes-Muñoz N,Chen J,Zhu H,Buchholz UJ,Moncman CL,Dutch RE

    更新日期:2016-09-28 00:00:00

  • Apolipoprotein E is an HIV-1-inducible inhibitor of viral production and infectivity in macrophages.

    abstract::Apolipoprotein E (ApoE) belongs to a class of cellular proteins involved in lipid metabolism. ApoE is a polymorphic protein produced primarily in macrophages and astrocytes. Different isoforms of ApoE have been associated with susceptibility to various diseases including Alzheimer's and cardiovascular diseases. ApoE e...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1007372

    authors: Siddiqui R,Suzu S,Ueno M,Nasser H,Koba R,Bhuyan F,Noyori O,Hamidi S,Sheng G,Yasuda-Inoue M,Hishiki T,Sukegawa S,Miyagi E,Strebel K,Matsushita S,Shimotohno K,Ariumi Y

    更新日期:2018-11-29 00:00:00

  • Critical role of Bcr1-dependent adhesins in C. albicans biofilm formation in vitro and in vivo.

    abstract::The fungal pathogen Candida albicans is frequently associated with catheter-based infections because of its ability to form resilient biofilms. Prior studies have shown that the transcription factor Bcr1 governs biofilm formation in an in vitro catheter model. However, the mechanistic role of the Bcr1 pathway and its ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.0020063

    authors: Nobile CJ,Andes DR,Nett JE,Smith FJ,Yue F,Phan QT,Edwards JE,Filler SG,Mitchell AP

    更新日期:2006-07-01 00:00:00

  • Lipopolysaccharide O structure of adherent and invasive Escherichia coli regulates intestinal inflammation via complement C3.

    abstract::Gut dysbiosis associated with intestinal inflammation is characterized by the blooming of particular bacteria such as adherent-invasive E. coli (AIEC). However, the precise mechanisms by which AIEC impact on colitis remain largely unknown. Here we show that antibiotic-induced dysbiosis worsened chemically-induced coli...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1008928

    authors: Ohno M,Hasegawa M,Hayashi A,Caballero-Flores G,Alteri CJ,Lawley TD,Kamada N,Núñez G,Inohara N

    更新日期:2020-10-07 00:00:00

  • Reconstruction of the cell entry pathway of an extinct virus.

    abstract::Endogenous retroviruses (ERVs), remnants of ancient germline infections, comprise 8% of the human genome. The most recently integrated includes human ERV-K (HERV-K) where several envelope (env) sequences remain intact. Viral pseudotypes decorated with one of those Envs are infectious. Using a recombinant vesicular sto...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1007123

    authors: Robinson-McCarthy LR,McCarthy KR,Raaben M,Piccinotti S,Nieuwenhuis J,Stubbs SH,Bakkers MJG,Whelan SPJ

    更新日期:2018-08-06 00:00:00

  • NFAT5 regulates HIV-1 in primary monocytes via a highly conserved long terminal repeat site.

    abstract::To replicate, HIV-1 capitalizes on endogenous cellular activation pathways resulting in recruitment of key host transcription factors to its viral enhancer. RNA interference has been a powerful tool for blocking key checkpoints in HIV-1 entry into cells. Here we apply RNA interference to HIV-1 transcription in primary...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.0020130

    authors: Ranjbar S,Tsytsykova AV,Lee SK,Rajsbaum R,Falvo JV,Lieberman J,Shankar P,Goldfeld AE

    更新日期:2006-12-01 00:00:00

  • VE-cadherin cleavage by LasB protease from Pseudomonas aeruginosa facilitates type III secretion system toxicity in endothelial cells.

    abstract::Infection of the vascular system by Pseudomonas aeruginosa (Pa) occurs during bacterial dissemination in the body or in blood-borne infections. Type 3 secretion system (T3SS) toxins from Pa induce a massive retraction when injected into endothelial cells. Here, we addressed the role of type 2 secretion system (T2SS) e...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1003939

    authors: Golovkine G,Faudry E,Bouillot S,Voulhoux R,Attrée I,Huber P

    更新日期:2014-03-13 00:00:00

  • Replication of CMV in the gut of HIV-infected individuals and epithelial barrier dysfunction.

    abstract::Although invasive cytomegalovirus (CMV) disease is uncommon in the era of antiretroviral therapy (ART), asymptomatic CMV coinfection is nearly ubiquitous in HIV infected individuals. While microbial translocation and gut epithelial barrier dysfunction may promote persistent immune activation in treated HIV infection, ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1006202

    authors: Maidji E,Somsouk M,Rivera JM,Hunt PW,Stoddart CA

    更新日期:2017-02-27 00:00:00

  • Disruption of Specific RNA-RNA Interactions in a Double-Stranded RNA Virus Inhibits Genome Packaging and Virus Infectivity.

    abstract::Bluetongue virus (BTV) causes hemorrhagic disease in economically important livestock. The BTV genome is organized into ten discrete double-stranded RNA molecules (S1-S10) which have been suggested to follow a sequential packaging pathway from smallest to largest segment during virus capsid assembly. To substantiate a...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1005321

    authors: Fajardo T Jr,Sung PY,Roy P

    更新日期:2015-12-08 00:00:00