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Article ; Online: Discovery of the Potent and Selective ATR Inhibitor Camonsertib (RP-3500).

Black, W Cameron / Abdoli, Abbas / An, Xiuli / Auger, Anick / Beaulieu, Patrick / Bernatchez, Michel / Caron, Cathy / Chefson, Amandine / Crane, Sheldon / Diallo, Mohamed / Dorich, Stéphane / Fader, Lee D / Ferraro, Gino B / Fournier, Sara / Gao, Qi / Ginzburg, Yelena / Hamel, Martine / Han, Yongshuai / Jones, Paul /

Lanoix, Stéphanie / Lacbay, Cyrus M / Leclaire, Marie-Eve / Levy, Maayan / Mamane, Yael / Mulani, Amina / Papp, Robert / Pellerin, Charles / Picard, Audrey / Skeldon, Alexander / Skorey, Kathryn / Stocco, Rino / St-Onge, Miguel / Truchon, Jean-François / Truong, Vouy Linh / Zimmermann, Michal / Zinda, Michael / Roulston, Anne

Journal of medicinal chemistry

2024 Volume 67, Issue 4, Page(s) 2349–2368

Abstract: ATR is a key kinase in the DNA-damage response (DDR) that is synthetic lethal with several other DDR proteins, making it an attractive target for the treatment of genetically selected solid tumors. Herein we describe the discovery of a novel ATR ... ...

Abstract	ATR is a key kinase in the DNA-damage response (DDR) that is synthetic lethal with several other DDR proteins, making it an attractive target for the treatment of genetically selected solid tumors. Herein we describe the discovery of a novel ATR inhibitor guided by a pharmacophore model to position a key hydrogen bond. Optimization was driven by potency and selectivity over the related kinase mTOR, resulting in the identification of camonsertib (RP-3500) with high potency and excellent ADME properties. Preclinical evaluation focused on the impact of camonsertib on myelosuppression, and an exploration of intermittent dosing schedules to allow recovery of the erythroid compartment and mitigate anemia. Camonsertib is currently undergoing clinical evaluation both as a single agent and in combination with talazoparib, olaparib, niraparib, lunresertib, or gemcitabine (NCT04497116, NCT04972110, NCT04855656). A preliminary recommended phase 2 dose for monotherapy was identified as 160 mg QD given 3 days/week.
MeSH term(s)	Humans ; Ataxia Telangiectasia Mutated Proteins ; Neoplasms/drug therapy ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Gemcitabine
Chemical Substances	Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; Protein Kinase Inhibitors ; Gemcitabine ; ATR protein, human (EC 2.7.11.1)
Language	English
Publishing date	2024-02-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.3c01917
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Article ; Online: Caspases and inflammasomes in metabolic inflammation.

Skeldon, Alexander M / Faraj, May / Saleh, Maya

Immunology and cell biology

2014 Volume 92, Issue 4, Page(s) 304–313

Abstract: Inflammation is an important contributor to the development of metabolic disease. Recent work has strongly implicated the inflammasome and caspase-1 as having a pivotal role in the regulation of metabolism, obesity, insulin resistance and cardiovascular ... ...

Abstract	Inflammation is an important contributor to the development of metabolic disease. Recent work has strongly implicated the inflammasome and caspase-1 as having a pivotal role in the regulation of metabolism, obesity, insulin resistance and cardiovascular disease. Through multiple murine and human studies we now know that the inflammasome can be activated by metabolic triggers in vivo. Clinical studies also reveal the inflammasome to be a potential candidate for therapeutic intervention and provide a clear incentive for future work on this inflammatory pathway.
MeSH term(s)	Animals ; Caspases/metabolism ; Cytokines/metabolism ; Disease ; Humans ; Immunity ; Inflammasomes/metabolism ; Inflammation/enzymology ; Inflammation/immunology ; Inflammation/metabolism ; Inflammation/therapy
Chemical Substances	Cytokines ; Inflammasomes ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2014-02-11
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	284057-1
ISSN	1440-1711 ; 0818-9641
ISSN (online)	1440-1711
ISSN	0818-9641
DOI	10.1038/icb.2014.5
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Article ; Online: Guiding ATR and PARP inhibitor combinationswith chemogenomic screens.

Zimmermann, Michal / Bernier, Cynthia / Kaiser, Beatrice / Fournier, Sara / Li, Li / Desjardins, Jessica / Skeldon, Alexander / Rimkunas, Victoria / Veloso, Artur / Young, Jordan T F / Roulston, Anne / Zinda, Michael

Cell reports

2022 Volume 40, Issue 2, Page(s) 111081

Abstract: Combinations of ataxia telangiectasia- and Rad3-related kinase inhibitors (ATRis) and poly(ADP-ribose) polymerase inhibitors (PARPis) synergistically kill tumor cells through modulation of complementary DNA repair pathways, but their tolerability is ... ...

Abstract	Combinations of ataxia telangiectasia- and Rad3-related kinase inhibitors (ATRis) and poly(ADP-ribose) polymerase inhibitors (PARPis) synergistically kill tumor cells through modulation of complementary DNA repair pathways, but their tolerability is limited by hematological toxicities. To address this, we performed a genome-wide CRISPR-Cas9 screen to identify genetic alterations that hypersensitize cells to a combination of the ATRi RP-3500 with PARPi, including deficiency in RNase H2, RAD51 paralog mutations, or the "alternative lengthening of telomeres" telomere maintenance mechanism. We show that RP-3500 and PARPi combinations kill cells carrying these genetic alterations at doses sub-therapeutic as single agents. We also demonstrate the mechanism of combination hypersensitivity in RNase H2-deficient cells, where we observe an irreversible replication catastrophe, allowing us to design a highly efficacious and tolerable in vivo dosing schedule. We present a comprehensive dataset to inform development of ATRi and PARPi combinations and an experimental framework applicable to other drug combination strategies.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Drug Resistance, Neoplasm ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Protein Kinase Inhibitors/pharmacology ; Ribonucleases
Chemical Substances	Antineoplastic Agents ; Poly(ADP-ribose) Polymerase Inhibitors ; Protein Kinase Inhibitors ; Ribonucleases (EC 3.1.-)
Language	English
Publishing date	2022-07-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2022.111081
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Article ; Online: The inflammasomes: molecular effectors of host resistance against bacterial, viral, parasitic, and fungal infections.

Skeldon, Alexander / Saleh, Maya

Frontiers in microbiology

2011 Volume 2, Page(s) 15

Abstract: The inflammasomes are large multi-protein complexes scaffolded by cytosolic pattern recognition receptors (PRRs) that form an important part of the innate immune system. They are activated following the recognition of microbial-associated molecular ... ...

Abstract	The inflammasomes are large multi-protein complexes scaffolded by cytosolic pattern recognition receptors (PRRs) that form an important part of the innate immune system. They are activated following the recognition of microbial-associated molecular patterns or host-derived danger signals (danger-associated molecular patterns) by PRRs. This recognition results in the recruitment and activation of the pro-inflammatory protease caspase-1, which cleaves its preferred substrates pro-interleukin-1β (IL-1β) and pro-IL-18 into their mature biologically active cytokine forms. Through processing of a number of other cellular substrates, caspase-1 is also required for the release of "alarmins" and the induction and execution of an inflammatory form of cell death termed pyroptosis. A growing spectrum of inflammasomes have been identified in the host defense against a variety of pathogens. Reciprocally, pathogens have evolved effector strategies to antagonize the inflammasome pathway. In this review we discuss recent developments in the understanding of inflammasome-mediated recognition of bacterial, viral, parasitic, and fungal infections and the beneficial or detrimental effects of inflammasome signaling in host resistance.
Language	English
Publishing date	2011-02-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587354-4
ISSN	1664-302X ; 1664-302X
ISSN (online)	1664-302X
ISSN	1664-302X
DOI	10.3389/fmicb.2011.00015
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Article ; Online: Construction of aminoglycoside-sensitive Burkholderia cenocepacia strains for use in studies of intracellular bacteria with the gentamicin protection assay.

Hamad, Mohamad A / Skeldon, Alexander M / Valvano, Miguel A

Applied and environmental microbiology

2010 Volume 76, Issue 10, Page(s) 3170–3176

Abstract: Burkholderia cenocepacia is a multidrug-resistant opportunistic pathogen that infects the airways of patients with cystic fibrosis (CF) and can survive intracellularly in macrophages and epithelial cells. The gentamicin protection assay, which relies on ... ...

Abstract	Burkholderia cenocepacia is a multidrug-resistant opportunistic pathogen that infects the airways of patients with cystic fibrosis (CF) and can survive intracellularly in macrophages and epithelial cells. The gentamicin protection assay, which relies on the poor ability of gentamicin or other aminoglycosides to permeate eukaryotic cell membranes, is traditionally employed to quantify intracellular bacteria. However, the high resistance of these bacteria to aminoglycosides hampers the use of the gentamicin protection assay to investigate intracellular infection by B. cenocepacia. Here, we report the construction of gentamicin-sensitive strains of B. cenocepacia carrying a deletion of the BCAL1674, BCAL1675, and BCAL1676 genes that form an operon encoding an AmrAB-OprA-like efflux pump. We show that bacteria carrying this deletion are hypersensitive to gentamicin and also delay phagolysosomal fusion upon infection of RAW 264.7 murine macrophages, as previously demonstrated for the parental strain. We also demonstrate for the first time that low concentrations of gentamicin can be used to effectively kill extracellular bacteria and reliably quantify the intracellular infection by B. cenocepacia, which can replicate in RAW 264.7 macrophages.
MeSH term(s)	Aminoglycosides/pharmacology ; Animals ; Anti-Bacterial Agents/pharmacology ; Burkholderia cepacia complex/drug effects ; Burkholderia cepacia complex/genetics ; Burkholderia cepacia complex/growth & development ; Gentamicins/pharmacology ; Humans ; Macrophages/microbiology ; Mice ; Microbial Sensitivity Tests ; Phagosomes/microbiology
Chemical Substances	Aminoglycosides ; Anti-Bacterial Agents ; Gentamicins
Language	English
Publishing date	2010-03-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	223011-2
ISSN	1098-5336 ; 0099-2240
ISSN (online)	1098-5336
ISSN	0099-2240
DOI	10.1128/AEM.03024-09
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Article ; Online: Caspase-12, but Not Caspase-11, Inhibits Obesity and Insulin Resistance.

Skeldon, Alexander M / Morizot, Alexandre / Douglas, Todd / Santoro, Nicola / Kursawe, Romy / Kozlitina, Julia / Caprio, Sonia / Mehal, Wajahat Z / Saleh, Maya

Journal of immunology (Baltimore, Md. : 1950)

2015 Volume 196, Issue 1, Page(s) 437–447

Abstract: Inflammation is well established to significantly impact metabolic diseases. The inflammatory protease caspase-1 has been implicated in metabolic dysfunction; however, a potential role for the related inflammatory caspases is currently unknown. In this ... ...

Abstract	Inflammation is well established to significantly impact metabolic diseases. The inflammatory protease caspase-1 has been implicated in metabolic dysfunction; however, a potential role for the related inflammatory caspases is currently unknown. In this study, we investigated a role for caspase-11 and caspase-12 in obesity and insulin resistance. Loss of caspase-12 in two independently generated mouse strains predisposed mice to develop obesity, metabolic inflammation, and insulin resistance, whereas loss of caspase-11 had no effect. The use of bone marrow chimeras determined that deletion of caspase-12 in the radio-resistant compartment was responsible for this metabolic phenotype. The Nlrp3 inflammasome pathway mediated the metabolic syndrome of caspase-12-deficient mice as ablation of Nlrp3 reversed Casp12(-/-) mice obesity phenotype. Although the majority of people lack a functional caspase-12 because of a T(125) single nucleotide polymorphism that introduces a premature stop codon, a fraction of African descendents express full-length caspase-12. Expression of caspase-12 was linked to decreased systemic and adipose tissue inflammation in a cohort of African American obese children. However, analysis of the Dallas Heart Study African American cohort indicated that the coding T(125)C single nucleotide polymorphism was not associated with metabolic parameters in humans, suggesting that host-specific differences mediate the expressivity of metabolic disease.
MeSH term(s)	Animals ; Carrier Proteins/genetics ; Carrier Proteins/immunology ; Caspase 12/genetics ; Caspase 12/physiology ; Caspases/genetics ; Caspases/physiology ; Caspases, Initiator ; Glucose Intolerance/genetics ; Humans ; Inflammation/genetics ; Inflammation/immunology ; Insulin Resistance/genetics ; Male ; Mice ; Mice, Knockout ; NLR Family, Pyrin Domain-Containing 3 Protein ; Obesity/genetics ; Polymorphism, Single Nucleotide/genetics ; Receptor-Interacting Protein Serine-Threonine Kinase 2 ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics
Chemical Substances	Carrier Proteins ; NLR Family, Pyrin Domain-Containing 3 Protein ; Nlrp3 protein, mouse ; Receptor-Interacting Protein Serine-Threonine Kinase 2 (EC 2.7.11.1) ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Ripk2 protein, mouse (EC 2.7.11.1) ; CASP12 protein, human (EC 3.4.22.-) ; Casp12 protein, mouse (EC 3.4.22.-) ; Casp4 protein, mouse (EC 3.4.22.-) ; Caspase 12 (EC 3.4.22.-) ; Caspases (EC 3.4.22.-) ; Caspases, Initiator (EC 3.4.22.-)
Language	English
Publishing date	2015-11-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1501529
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Article ; Online: The Type VI secretion system of Burkholderia cenocepacia affects multiple Rho family GTPases disrupting the actin cytoskeleton and the assembly of NADPH oxidase complex in macrophages.

Rosales-Reyes, Roberto / Skeldon, Alexander M / Aubert, Daniel F / Valvano, Miguel A

Cellular microbiology

2012 Volume 14, Issue 2, Page(s) 255–273

Abstract: Burkholderia cenocepacia is a Gram-negative opportunistic pathogen of patients with cystic fibrosis and chronic granulomatous disease. The bacterium survives intracellularly in macrophages within a membrane-bound vacuole (BcCV) that precludes the fusion ... ...

Abstract	Burkholderia cenocepacia is a Gram-negative opportunistic pathogen of patients with cystic fibrosis and chronic granulomatous disease. The bacterium survives intracellularly in macrophages within a membrane-bound vacuole (BcCV) that precludes the fusion with lysosomes. The underlying cellular mechanisms and bacterial molecules mediating these phenotypes are unknown. Here, we show that intracellular B. cenocepacia expressing a type VI secretion system (T6SS) affects the activation of the Rac1 and Cdc42 RhoGTPase by reducing the cellular pool of GTP-bound Rac1 and Cdc42. The T6SS also increases the cellular pool of GTP-bound RhoA and decreases cofilin activity. These effects lead to abnormal actin polymerization causing collapse of lamellipodia and failure to retract the uropod. The T6SS also prevents the recruitment of soluble subunits of the NADPH oxidase complex including Rac1 to the BcCV membrane, but is not involved in the BcCV maturation arrest. Therefore, T6SS-mediated deregulation of Rho family GTPases is a common mechanism linking disruption of the actin cytoskeleton and delayed NADPH oxidase activation in macrophages infected with B. cenocepacia.
MeSH term(s)	Actin Cytoskeleton/metabolism ; Animals ; Burkholderia cenocepacia/pathogenicity ; Cell Line ; Guanosine Triphosphate/metabolism ; Macrophages/enzymology ; Macrophages/metabolism ; Macrophages/microbiology ; Mice ; Models, Biological ; NADPH Oxidases/antagonists & inhibitors ; Neuropeptides/antagonists & inhibitors ; cdc42 GTP-Binding Protein/antagonists & inhibitors ; rac GTP-Binding Proteins/antagonists & inhibitors ; rac1 GTP-Binding Protein ; rhoA GTP-Binding Protein/metabolism
Chemical Substances	Neuropeptides ; Rac1 protein, mouse ; Guanosine Triphosphate (86-01-1) ; NADPH Oxidases (EC 1.6.3.-) ; cdc42 GTP-Binding Protein (EC 3.6.5.2) ; rac GTP-Binding Proteins (EC 3.6.5.2) ; rac1 GTP-Binding Protein (EC 3.6.5.2) ; rhoA GTP-Binding Protein (EC 3.6.5.2)
Language	English
Publishing date	2012-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1468320-9
ISSN	1462-5822 ; 1462-5814
ISSN (online)	1462-5822
ISSN	1462-5814
DOI	10.1111/j.1462-5822.2011.01716.x
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Article ; Online: Cellular inhibitor of apoptosis protein cIAP2 protects against pulmonary tissue necrosis during influenza virus infection to promote host survival.

Rodrigue-Gervais, Ian Gaël / Labbé, Katherine / Dagenais, Maryse / Dupaul-Chicoine, Jeremy / Champagne, Claudia / Morizot, Alexandre / Skeldon, Alexander / Brincks, Erik L / Vidal, Silvia M / Griffith, Thomas S / Saleh, Maya

Cell host & microbe

2014 Volume 15, Issue 1, Page(s) 23–35

Abstract: Cellular inhibitors of apoptosis proteins (cIAPs) are essential regulators of cell death and immunity. The corresponding contributions of IAPs to infectious disease outcomes are relatively unexplored. We find that mice deficient in cIAP2 exhibit ... ...

Abstract	Cellular inhibitors of apoptosis proteins (cIAPs) are essential regulators of cell death and immunity. The corresponding contributions of IAPs to infectious disease outcomes are relatively unexplored. We find that mice deficient in cIAP2 exhibit increased susceptibility and mortality to influenza A virus infection. The lethality was not due to impaired antiviral immune functions, but rather because of death-receptor-induced programmed necrosis of airway epithelial cells that led to severe bronchiole epithelial degeneration, despite control of viral replication. Pharmacological inhibition of RIPK1 or genetic deletion of Ripk3, both kinases involved in programmed necrosis, rescued cIAP2-deficient mice from influenza-induced lethality. Genetic deletion of the death receptor agonists Fas ligand or TRAIL from the hematopoietic compartment also reversed the susceptibility of cIAP2-deficient mice. Thus, cIAP2-dependent antagonism of RIPK3-mediated programmed necrosis critically protects the host from influenza infection through maintenance of pulmonary tissue homeostasis rather than through pathogen control by the immune system.
MeSH term(s)	Animals ; Baculoviral IAP Repeat-Containing 3 Protein ; Fas Ligand Protein/deficiency ; Fas Ligand Protein/genetics ; Fas Ligand Protein/immunology ; Gene Expression Regulation ; Homeostasis/immunology ; Host-Pathogen Interactions ; Humans ; Immunity, Innate ; Influenza A Virus, H1N1 Subtype/immunology ; Inhibitor of Apoptosis Proteins/deficiency ; Inhibitor of Apoptosis Proteins/genetics ; Inhibitor of Apoptosis Proteins/immunology ; Lung/immunology ; Lung/pathology ; Lung/virology ; Mice ; Mice, Knockout ; Necrosis/complications ; Necrosis/genetics ; Necrosis/immunology ; Necrosis/mortality ; Orthomyxoviridae Infections/complications ; Orthomyxoviridae Infections/genetics ; Orthomyxoviridae Infections/immunology ; Orthomyxoviridae Infections/mortality ; Protein Kinase Inhibitors/pharmacology ; Receptor-Interacting Protein Serine-Threonine Kinases/antagonists & inhibitors ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics ; Receptor-Interacting Protein Serine-Threonine Kinases/immunology ; Respiratory Mucosa/immunology ; Respiratory Mucosa/pathology ; Respiratory Mucosa/virology ; Signal Transduction ; Survival Analysis ; TNF-Related Apoptosis-Inducing Ligand/deficiency ; TNF-Related Apoptosis-Inducing Ligand/genetics ; TNF-Related Apoptosis-Inducing Ligand/immunology ; Ubiquitin-Protein Ligases
Chemical Substances	Fas Ligand Protein ; Fasl protein, mouse ; Inhibitor of Apoptosis Proteins ; Protein Kinase Inhibitors ; TNF-Related Apoptosis-Inducing Ligand ; Tnfsf10 protein, mouse ; Baculoviral IAP Repeat-Containing 3 Protein (EC 2.3.2.27) ; Birc3 protein, mouse (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Ripk1 protein, mouse (EC 2.7.11.1) ; Ripk3 protein, mouse (EC 2.7.11.1)
Language	English
Publishing date	2014-01-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2278004-X
ISSN	1934-6069 ; 1931-3128
ISSN (online)	1934-6069
ISSN	1931-3128
DOI	10.1016/j.chom.2013.12.003
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Article ; Online: RP-3500: A Novel, Potent, and Selective ATR Inhibitor that is Effective in Preclinical Models as a Monotherapy and in Combination with PARP Inhibitors.

Roulston, Anne / Zimmermann, Michal / Papp, Robert / Skeldon, Alexander / Pellerin, Charles / Dumas-Bérube, Émilie / Dumais, Valerie / Dorich, Stéphane / Fader, Lee D / Fournier, Sara / Li, Li / Leclaire, Marie-Eve / Yin, Shou Yun / Chefson, Amandine / Alam, Hunain / Yang, William / Fugère-Desjardins, Chloe / Vignini-Hammond, Sabrina / Skorey, Kathryn /

Mulani, Amina / Rimkunas, Victoria / Veloso, Artur / Hamel, Martine / Stocco, Rino / Mamane, Yael / Li, Zuomei / Young, Jordan T F / Zinda, Michael / Black, W Cameron

Molecular cancer therapeutics

2021 Volume 21, Issue 2, Page(s) 245–256

Abstract: Ataxia telangiectasia and Rad3-related (ATR) kinase protects genome integrity during DNA replication. RP-3500 is a novel, orally bioavailable clinical-stage ATR kinase inhibitor (NCT04497116). RP-3500 is highly potent with ... ...

Abstract	Ataxia telangiectasia and Rad3-related (ATR) kinase protects genome integrity during DNA replication. RP-3500 is a novel, orally bioavailable clinical-stage ATR kinase inhibitor (NCT04497116). RP-3500 is highly potent with IC
MeSH term(s)	Ataxia Telangiectasia ; Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors ; DNA-Activated Protein Kinase/metabolism ; Humans ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors ; Protein Kinase Inhibitors ; ATR protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; DNA-Activated Protein Kinase (EC 2.7.11.1)
Language	English
Publishing date	2021-12-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-21-0615
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Article: Construction of Aminoglycoside-Sensitive Burkholderia cenocepacia Strains for Use in Studies of Intracellular Bacteria with the Gentamicin Protection Assay

Hamad, Mohamad A / Skeldon, Alexander M / Valvano, Miguel A

Applied and environmental microbiology. 2010 May 15, v. 76, no. 10

2010

Abstract	Burkholderia cenocepacia is a multidrug-resistant opportunistic pathogen that infects the airways of patients with cystic fibrosis (CF) and can survive intracellularly in macrophages and epithelial cells. The gentamicin protection assay, which relies on the poor ability of gentamicin or other aminoglycosides to permeate eukaryotic cell membranes, is traditionally employed to quantify intracellular bacteria. However, the high resistance of these bacteria to aminoglycosides hampers the use of the gentamicin protection assay to investigate intracellular infection by B. cenocepacia. Here, we report the construction of gentamicin-sensitive strains of B. cenocepacia carrying a deletion of the BCAL1674, BCAL1675, and BCAL1676 genes that form an operon encoding an AmrAB-OprA-like efflux pump. We show that bacteria carrying this deletion are hypersensitive to gentamicin and also delay phagolysosomal fusion upon infection of RAW 264.7 murine macrophages, as previously demonstrated for the parental strain. We also demonstrate for the first time that low concentrations of gentamicin can be used to effectively kill extracellular bacteria and reliably quantify the intracellular infection by B. cenocepacia, which can replicate in RAW 264.7 macrophages.
Keywords	Burkholderia ; bacteria ; cell membranes ; cystic fibrosis ; epithelial cells ; eukaryotic cells ; gentamicin ; macrophages ; operon ; pathogens ; patients ; transporters
Language	English
Dates of publication	2010-0515
Size	p. 3170-3176.
Publishing place	American Society for Microbiology
Document type	Article
Note	Includes references
ZDB-ID	223011-2
ISSN	1098-5336 ; 0099-2240
ISSN (online)	1098-5336
ISSN	0099-2240
DOI	10.1128/AEM.03024-09
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