Current perspective of ATP synthase inhibitors in the management of the tuberculosis

2021 ◽  
Vol 21 ◽  
Author(s):  
KM Divita ◽  
Gopal L. Khatik
Keyword(s):  
Atp Synthase ◽  
Recent Literature ◽  
Atp Production ◽  
Drug Of Choice ◽  
Current Perspective ◽  
Alternative Approach ◽  
Mdr Tb ◽  
C Subunit ◽  
Life Threatening ◽  
Synthase Inhibitor

Introduction: Tuberculosis is a life-threatening disease, and the drugs discovered during the era of 1950 and 1970 are found inefficient due to emergent MDR and XDR-TB. Tuberculosis is difficult to treat due to the development of antibiotic resistance. ATP synthase is consisting of two units, F1 and F0 units. These are present in the cytoplasm and membrane of mitochondria, respectively. F1 unit comprises of a, b, and c subunit while F0 subunit has α, β, γ, δ, ε subunits. Bedaquiline is the first approved ATP synthase inhibitor in 2012 by USFDA. Methods: Recent literature from 2005-2020 were collected using Pubmed with the keywords ATP synthase inhibitor, bedaquiline derivatives, tuberculosis. The work describing detailed analyses of bedaquiline (BDQ) was included in the current work, and others were excluded. Results: ATP production occurs via the ATP synthase enzyme, leading to the growth and multiplication of mycobacteria. BDQ inhibits the mycobacterium ATP synthase enzyme, a heteropolymeric complex consisting of two subunits, but it does not interfere with mammalian ATP synthase. Bedaquiline (BDQ) has become a drug of choice to treat MDR-TB and help to reduce the treatment span. Recently observed triple mutation as wtLeu59A → mtVal59A; wtIle66A→ mtMet66A and wtGlu61B → mtAsp61B of ATP synthase led to decrease BDQ binding affinity; thus, researchers are putting efforts for its newer derivative discovery. Conclusion: ATP synthase inhibitor could be an alternative approach for better treatment of tuberculosis. Herein we discussed the recent advancements in the development of newer analogues of BDQ with its future perspectives.

scholarly journals Structure of the mycobacterial ATP synthase Forotor ring in complex with the anti-TB drug bedaquiline

2015 ◽  
Vol 1 (4) ◽  
pp. e1500106 ◽  
Author(s):  
Laura Preiss ◽  
Julian D. Langer ◽  
Özkan Yildiz ◽  
Luise Eckhardt-Strelau ◽  
Jérôme E. G. Guillemont ◽  
...  
Keyword(s):  
Atp Synthase ◽  
Multidrug Resistant ◽  
Metabolic Enzyme ◽  
Structure Based Drug Design ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Atp Generation ◽  
Ion Binding Sites ◽  
Synthase Inhibitor

Multidrug-resistant tuberculosis (MDR-TB) is more prevalent today than at any other time in human history. Bedaquiline (BDQ), a novelMycobacterium-specific adenosine triphosphate (ATP) synthase inhibitor, is the first drug in the last 40 years to be approved for the treatment of MDR-TB. This bactericidal compound targets the membrane-embedded rotor (c-ring) of the mycobacterial ATP synthase, a key metabolic enzyme required for ATP generation. We report the x-ray crystal structures of a mycobacterial c9ring without and with BDQ bound at 1.55- and 1.7-Å resolution, respectively. The structures and supporting functional assays reveal how BDQ specifically interacts with the rotor ring via numerous interactions and thereby completely covers the c-ring’s ion-binding sites. This prevents the rotor ring from acting as an ion shuttle and stalls ATP synthase operation. The structures explain how diarylquinoline chemicals specifically inhibit the mycobacterial ATP synthase and thus enable structure-based drug design of next-generation ATP synthase inhibitors againstMycobacterium tuberculosisand other bacterial pathogens.

scholarly journals Bedaquiline, an FDA-approved drug, inhibits mitochondrial ATP production and metastasis in vivo, by targeting the gamma subunit (ATP5F1C) of the ATP synthase

2021 ◽  
Author(s):  
Marco Fiorillo ◽  
Cristian Scatena ◽  
Antonio Giuseppe Naccarato ◽  
Federica Sotgia ◽  
Michael P. Lisanti
Keyword(s):  
Cell Migration ◽  
Treatment Failure ◽  
Atp Synthase ◽  
Atp Depletion ◽  
Multi Drug Resistance ◽  
Gamma Subunit ◽  
Primary Tumors ◽  
Atp Production ◽  
Mitochondrial Atp Synthase

AbstractHere, we provide evidence that high ATP production by the mitochondrial ATP-synthase is a new therapeutic target for anticancer therapy, especially for preventing tumor progression. More specifically, we isolated a subpopulation of ATP-high cancer cells which are phenotypically aggressive and demonstrate increases in proliferation, stemness, anchorage-independence, cell migration, invasion and multi-drug resistance, as well as high antioxidant capacity. Clinically, these findings have important implications for understanding treatment failure and cancer cell dormancy. Using bioinformatic analysis of patient samples, we defined a mitochondrial-related gene signature for metastasis, which features the gamma-subunit of the mitochondrial ATP-synthase (ATP5F1C). The relationship between ATP5F1C protein expression and metastasis was indeed confirmed by immunohistochemistry. Next, we used MDA-MB-231 cells as a model system to functionally validate these findings. Importantly, ATP-high MDA-MB-231 cells showed a nearly fivefold increase in metastatic capacity in vivo. Consistent with these observations, ATP-high cells overexpressed (i) components of mitochondrial complexes I–V, including ATP5F1C, and (ii) markers associated with circulating tumor cells (CTCs) and metastasis, such as EpCAM and VCAM1. Knockdown of ATP5F1C expression significantly reduced ATP-production, anchorage-independent growth, and cell migration, as predicted. Similarly, therapeutic administration of the FDA-approved drug, Bedaquiline, downregulated ATP5F1C expression in vitro and prevented spontaneous metastasis in vivo. In contrast, Bedaquiline had no effect on the growth of non-tumorigenic mammary epithelial cells (MCF10A) or primary tumors in vivo. Taken together, our results suggest that mitochondrial ATP depletion is a new therapeutic strategy for metastasis prophylaxis, to avoid treatment failure. In summary, we conclude that mitochondrial ATP5F1C is a promising new biomarker and molecular target for future drug development, for the prevention of metastatic disease progression.

scholarly journals Crystallographic structure of the turbine C-ring from spinach chloroplast F-ATP synthase

2014 ◽  
Vol 34 (2) ◽  
Author(s):  
Asha Manikkoth Balakrishna ◽  
Holger Seelert ◽  
Sven-Hendric Marx ◽  
Norbert A. Dencher ◽  
Gerhard Grüber
Keyword(s):  
Atp Synthase ◽  
Ring Width ◽  
Atp Synthesis ◽  
Crystallographic Structure ◽  
Unit Cell Parameters ◽  
Subunit C ◽  
Cell Parameters ◽  
Ring Diameter ◽  
C Subunit

In eukaryotic and prokaryotic cells, F-ATP synthases provide energy through the synthesis of ATP. The chloroplast F-ATP synthase (CF1FO-ATP synthase) of plants is integrated into the thylakoid membrane via its FO-domain subunits a, b, b’ and c. Subunit c with a stoichiometry of 14 and subunit a form the gate for H+-pumping, enabling the coupling of electrochemical energy with ATP synthesis in the F1 sector. Here we report the crystallization and structure determination of the c14-ring of subunit c of the CF1FO-ATP synthase from spinach chloroplasts. The crystals belonged to space group C2, with unit-cell parameters a=144.420, b=99.295, c=123.51 Å, and β=104.34° and diffracted to 4.5 Å resolution. Each c-ring contains 14 monomers in the asymmetric unit. The length of the c-ring is 60.32 Å, with an outer ring diameter 52.30 Å and an inner ring width of 40 Å.

scholarly journals Genome-Wide Screening Identifies Six Genes That Are Associated with Susceptibility to Escherichia coli Microcin PDI

2015 ◽  
Vol 81 (20) ◽  
pp. 6953-6963 ◽  
Author(s):  
Zhe Zhao ◽  
Lauren J. Eberhart ◽  
Lisa H. Orfe ◽  
Shao-Yeh Lu ◽  
Thomas E. Besser ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Atp Synthase ◽  
Disulfide Bonds ◽  
Gene Knockout ◽  
Single Gene ◽  
Site Directed Mutagenesis ◽  
Content Type ◽  
E Coli ◽  
Synthase Inhibitor ◽  
Loss Of Susceptibility

ABSTRACTThe microcin PDI inhibits a diverse group of pathogenicEscherichia colistrains. Coculture of a single-gene knockout library (BW25113;n= 3,985 mutants) against a microcin PDI-producing strain (E. coli25) identified six mutants that were not susceptible (ΔatpA, ΔatpF, ΔdsbA, ΔdsbB, ΔompF, and ΔompR). Complementation of these genes restored susceptibility in all cases, and the loss of susceptibility was confirmed through independent gene knockouts inE. coliO157:H7 Sakai. Heterologous expression ofE. coliompFconferred susceptibility toSalmonella entericaandYersinia enterocoliticastrains that are normally unaffected by microcin PDI. The expression of chimeric OmpF and site-directed mutagenesis revealed that the K47G48N49region within the first extracellular loop ofE. coliOmpF is a putative binding site for microcin PDI. OmpR is a transcriptional regulator forompF, and consequently loss of susceptibility by the ΔompRstrain most likely is related to this function. Deletion of AtpA and AtpF, as well as AtpE and AtpH (missed in the original library screen), resulted in the loss of susceptibility to microcin PDI and the loss of ATP synthase function. Coculture of a susceptible strain in the presence of an ATP synthase inhibitor resulted in a loss of susceptibility, confirming that a functional ATP synthase complex is required for microcin PDI activity. Intransexpression ofompFin the ΔdsbAand ΔdsbBstrains did not restore a susceptible phenotype, indicating that these proteins are probably involved with the formation of disulfide bonds for OmpF or microcin PDI.

Dual Mutations Reveal Interactions Between Components of Oxidative Phosphorylation in Kluyveromyces lactis

Genetics ◽  
2001 ◽  
Vol 159 (3) ◽  
pp. 929-938
Author(s):  
G D Clark-Walker ◽  
X J Chen
Keyword(s):  
Electron Transport ◽  
Oxidative Phosphorylation ◽  
Atp Synthase ◽  
Kluyveromyces Lactis ◽  
Mitochondrial Protein ◽  
Proton Pumping ◽  
Nuclear Genes ◽  
Suppressor Activity ◽  
Inner Membrane ◽  
Atp Production

Abstract Loss of mtDNA or mitochondrial protein synthesis cannot be tolerated by wild-type Kluyveromyces lactis. The mitochondrial function responsible for ρ0-lethality has been identified by disruption of nuclear genes encoding electron transport and F0-ATP synthase components of oxidative phosphorylation. Sporulation of diploid strains heterozygous for disruptions in genes for the two components of oxidative phosphorylation results in the formation of nonviable spores inferred to contain both disruptions. Lethality of spores is thought to result from absence of a transmembrane potential, ΔΨ, across the mitochondrial inner membrane due to lack of proton pumping by the electron transport chain or reversal of F1F0-ATP synthase. Synergistic lethality, caused by disruption of nuclear genes, or ρ0-lethality can be suppressed by the atp2.1 mutation in the β-subunit of F1-ATPase. Suppression is viewed as occurring by an increased hydrolysis of ATP by mutant F1, allowing sufficient electrogenic exchange by the translocase of ADP in the matrix for ATP in the cytosol to maintain ΔΨ. In addition, lethality of haploid strains with a disruption of AAC encoding the ADP/ATP translocase can be suppressed by atp2.1. In this case suppression is considered to occur by mutant F1 acting in the forward direction to partially uncouple ATP production, thereby stimulating respiration and relieving detrimental hyperpolarization of the inner membrane. Participation of the ADP/ATP translocase in suppression of ρ0-lethality is supported by the observation that disruption of AAC abolishes suppressor activity of atp2.1.

scholarly journals Mitochondrial fusion mediated by mitofusin 1 regulates macrophage mycobactericidal activity by enhancing autophagy

2021 ◽  
Author(s):  
Yuping Ning ◽  
Yi Cai ◽  
Youchao Dai ◽  
Fuxiang Li ◽  
Siwei Mo ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Life Cycle ◽  
Atp Synthase ◽  
Host Defense ◽  
Mitochondrial Dynamics ◽  
Critical Role ◽  
Mitochondrial Fusion ◽  
Atp Production ◽  
Metabolism Pathway ◽  
Mitofusin 1

Mitochondria as a highly dynamic organelle continuously changes morphology and position during its life cycle. Mitochondrial dynamics including fission and fusion play a critical role in maintaining functional mitochondria for ATP production, which is directly linked to host defense against Mtb infection. However, how macrophages regulate mitochondrial dynamics during Mycobacterium tuberculosis (Mtb) infection remains elusive. In this study, we found that Mtb infection induced mitochondrial fusion through enhancing the expression of mitofusin 1 ( MFN1 ), which resulted in increased ATP production. Silencing MFN1 inhibited mitochondrial fusion and subsequently reduced ATP production, which, in turn, severely impaired macrophages mycobactericidal activity by inhibiting autophagy. Impairment of mycobactericidal activity and autophagy was replicated using oligomycin, an inhibitor of ATP synthase. In summary, our study revealed MFN1-mediated mitochondrial fusion is essential for macrophages mycobactericidal activity through the regulation of ATP dependent autophagy. MFN1-mediated metabolism pathway might be targets for development of host direct therapy (HDT) strategy against TB.

scholarly journals Clinical and Pharmacological Approaches to the Prescription of Centrally Acting Antihypertensive Drugs for Uncontrolled Arterial Hypertension

2020 ◽  
Vol 16 (5) ◽  
pp. 815-821
Author(s):  
A. V. Strygin ◽  
B. E. Tolkachev ◽  
A. O. Strygina ◽  
A. M. Dotsenko
Keyword(s):  
Arterial Hypertension ◽  
Antihypertensive Drugs ◽  
Hypotensive Effect ◽  
Optimal Choice ◽  
Clinical Settings ◽  
Hypertensive Urgency ◽  
Drug Of Choice ◽  
Target Organs ◽  
Life Threatening ◽  
Hypertensive Therapy

Episodes of rapid increase in blood pressure due to uncontrolled arterial hypertension, previously known as a hypertensive urgency, is common clinical condition which many of practicing physicians are encountered daily. As a rule, these conditions are not life-threatening, however they could lead to target-organs damage if not promptly relieved. Therefore, clear evidence-based recommendations of optimal antihypertensive drug administration in these situations would provide more safe and effective therapy. Despite that, definite expert consensus regarding optimal choice of antihypertensive drugs to manage these patients have not been reached so far. The aim of the current review was to assess the results obtained from clinical trials regarding the safety and efficacy of moxonidine for urgent hypertensive therapy in patients with uncontrolled arterial hypertension admitted to emergency healthcare units as well as in those at the prehospital stage. Performed literature-based analysis revealed enough evidences proving that moxonidine can be administered in a single dose of 0.4 mg as a drug of choice in situations where prompt and stable hypotensive effect is desired. Results of comparative studies designed to closely match real clinical settings indicate that more adequate and sustainable therapeutic effect is achieved after moxonidine administration in comparison to other frequently used antihypertensive drugs.

Abstract MP247: Mitochondrial Complex V Is Regulated By GRK2 In The Heart

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Kimberly Ferrero ◽  
Jessica M Pfleger ◽  
Kurt Chuprun ◽  
Eric Barr ◽  
Erhe Gao ◽  
...  
Keyword(s):  
Atp Synthase ◽  
Cardiac Injury ◽  
Atp Synthesis ◽  
Cardiac Metabolism ◽  
Neonatal Rat ◽  
Interacting Proteins ◽  
Atp Production

The GPCR kinase GRK2 is highly expressed the heart; importantly, during cardiac injury or heart failure (HF) both levels and activity of GRK2 increase. The role of GRK2 during HF is canonically studied upstream of β-adrenergic desensitization. However, GRK2 has a large interactome and noncanonical functions for this kinase are being uncovered. We have discovered that in the heart, GRK2 translocates to mitochondria ( mtGRK2 ) following injury and is associated with negative effects on cardiac metabolism. Thus, we have sought to identify the mechanism(s) by which GRK2 can regulate mitochondrial function. We hypothesize that mtGRK2 interacts with proteins which regulate bioenergetics and substrate utilization, and this never-before-described role may partially explain the altered mitochondrial phenotype seen following cardiac injury or HF. Stress-induced mitochondrial translocation of GRK2 was validated in neonatal rat ventricular myocytes, murine heart tissue and a cardiac-derived cell line. Consequently, the GRK2 interactome was mapped basally and under stress conditions in vitro, in vivo , and with tagged recombinant peptides. GRK2-interacting proteins were isolated via immunoprecipitation and analyzed via liquid chromatography-mass spectroscopy (LCMS). Proteomics analysis (IPA; Qiagen) identified mtGRK2 interacting proteins which were also involved in mitochondrial dysfunction. Excitingly, Complexes I, II, IV and V (ATP synthase) of the electron transport chain (ETC) were identified in the subset of mtGRK2-dysfunction partners. Several mtGRK2-ETC interactions were increased following stress, particularly those in Complex V. We further established that mtGRK2 phosphorylates some of the subunits of Complex V, particularly the ATP synthase barrel which is critical for ATP production in the heart. Specific amino acid residues on these subunits have been identified using PTM-LCMS and are currently being validated in a murine model of myocardial infarction. To support these data, we have also determined that alterations in either the levels or kinase activity of GRK2 appear to alter the enzymatic activity of Complex V in vitro , thus altering ATP production. In summary, the phosphorylation of the ATP synthesis machinery by mtGRK2 may be regulating some of the phenotypic effects of injured or failing hearts such as increased ROS production and reduced fatty acid metabolism. Research is ongoing in our lab to elucidate the novel role of GRK2 in regulating mitochondrial bioenergetics and cell death, thus uncovering an exciting, druggable novel target for rescuing cardiac function in patients with injured and/or failing hearts.

Dynamics of the Preterm Gut Microbiome in Health and Disease

2021 ◽  
Author(s):  
Alain C Cuna ◽  
Michael J Morowitz ◽  
Ishfaq Ahmed ◽  
Shahid Umar ◽  
Venkatesh Sampath
Keyword(s):  
Preterm Infants ◽  
Gut Microbiome ◽  
Recent Literature ◽  
Late Onset ◽  
Perinatal Period ◽  
Future Directions ◽  
Late Onset Sepsis ◽  
Microbiome Research ◽  
Life Threatening ◽  
Health And Disease

Advances in metagenomics have allowed a detailed study of the gut microbiome, and its role in human health and disease. Infants born prematurely possess a fragile gut microbial ecosystem that is vulnerable to perturbation. Alterations in the developing gut microbiome in preterm infants are linked to life-threatening diseases such as necrotizing enterocolitis (NEC) and late onset sepsis; and may impact future risk of asthma, atopy, obesity, and psychosocial disease. In this mini review, we summarize recent literature on the origins and patterns of development of the preterm gut microbiome in the perinatal period. The host-microbiome-environmental factors that portend development of dysbiotic intestinal microbial patterns associated with NEC and sepsis are reviewed. Strategies to manipulate the microbiome and mitigate dysbiosis, including the use of probiotics and prebiotics will also be discussed. Finally, we explore the challenges and future directions of gut microbiome research in preterm infants.

scholarly journals Cellular Mechanisms of Metabolic Remodeling During Fluid Sheer Stress-Induced Metastasis

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 322-322
Author(s):  
Tracie Dunn ◽  
Spenser Brown ◽  
Nelli Mnatsakanyan ◽  
Elizabeth Jonas ◽  
Kim Yonghyun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Energy Metabolism ◽  
Cancer Cells ◽  
Atp Synthase ◽  
Breast Cancer Cells ◽  
Transport Systems ◽  
Cellular Mechanisms ◽  
Sheer Stress ◽  
Metabolic Remodeling ◽  
C Subunit

Abstract Objectives Fluid sheer stress (FSS) is a physical stimuli of circulating tumor cells responsible for development of and progression to cancer. FSS is reported to enhance chemoresistance and proliferation in breast cancer cells. However, cellular mechanisms explaining how FSS contributes to the metastatic phenotype of breast cancer cell are less known. Chemoresistance is highly dependent upon active transport systems, and cell division and growth require ATP. In this study, we hypothesize that FSS contributes to mitochondrial remodeling and leads to alterations in energy metabolism which favor metastasis. Methods MDA-MB-231 human breast cancer cells were exposed to fluid sheer stress (FSS). MDA-MB-231 cells were then grown in culture media for 24 h, and intracellular energy (ATP) and abundance of ATP synthase were analyzed. Results FSS significantly increases intracellular ATP in MDA-MB-231 breast cancer cells. Interestingly, MDA-MB-231 cells retained increased ATP after treatment with the uncoupler FCCP indicating remodeling and decreased reliance on mitochondrial energy metabolism. We then quantified the abundance of ATP synthase, the key enzyme complex that produces mitochondrial ATP. FSS significantly decreased protein levels of the c-subunit of ATP synthase. Conclusions Our data show that FSS causes metabolic remodeling of mitochondria-dependent ATP production. We suggest that the c-subunit of ATP synthase is an important target of FSS-mediated metastasis. Strategies to enhance the abundance or activity of the c-subunit may prevent metabolic remodeling-associated with metastasis in FSS-exposed circulating cancer cells. Funding Sources Alabama Life Research Institute (ALRI) 14,565.

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