Transcriptional response of Mycobacterium tuberculosis to inhibition of Cytochrome bd oxidase and Cytochrome bcc:aa3 oxidase
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA667658 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR12779714.fastq.gz | Fastqsanger.gz | |||
| SRR12779715.fastq.gz | Fastqsanger.gz | |||
| SRR12779716.fastq.gz | Fastqsanger.gz | |||
| SRR12779717.fastq.gz | Fastqsanger.gz |
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Project description:Comparative analysis of the transcriptional response, as quantified by RNA-Seq, of Mycobacterium tuberculosis (Mtb) during inhibition of the terminal cytochrome oxidases, Cytochrome bd oxidase and Cytochrome bcc:aa3. This study was designed to evaluate the efficacy if a novel small molecule inhibitor of the Cytochrome bd oxidase. Specifically, we compared the transcriptional response of Mtb during inhibition by Q203 with a Cytochrome bd deletion mutant to the transcriptional response of Mtb treated with a combination of Q203 and the purported Cytorchomre bd small molecule inhibitor (ND-011992).
2020-10-07 | GSE159080 | GEO
Project description:The obligatory aerobic acetic acid bacterium Gluconobacter oxydans oxidizes a variety of substrates in the periplasm by membrane-bound dehydrogenases, which transfer the reducing equivalents to ubiquinone. Two quinol oxidases, cytochrome bo3 and cytochrome bd, then catalyze transfer of the electrons from ubiquinol to molecular oxygen. In this study, mutants lacking either of these terminal oxidases were characterized. Deletion of the cydAB genes for cytochrome bd had no obvious influence on growth, whereas the lack of the cyoBACD genes for cytochrome bo3 severely reduced the growth rate and the cell yield. Using a respiration activity monitoring system and adjusting different levels of oxygen availability, hints for a low oxygen affinity of cytochrome bd oxidase were obtained, which were supported by measurements of oxygen consumption in a respirometer. The H+/O ratio of the ΔcyoBACD mutant with mannitol as substrate was 0.56 ± 0.11 and more than 50% lower than that of the reference strain (1.26 ± 0.06) and the delta-cydAB mutant (1.31 ± 0.16), indicating that cytochrome bo3 oxidase is the main component for proton extrusion via the respiratory chain. Plasmid-based overexpression of cyoBACD led to increased growth rates and growth yields, both in the wild type and the delta-cyoBACD mutant, suggesting that cytochrome bo3 might be the rate-limiting factor of the respiratory chain.
2013-07-26 | GSE47782 | GEO
Project description:The obligatory aerobic acetic acid bacterium Gluconobacter oxydans oxidizes a variety of substrates in the periplasm by membrane-bound dehydrogenases, which transfer the reducing equivalents to ubiquinone. Two quinol oxidases, cytochrome bo3 and cytochrome bd, then catalyze transfer of the electrons from ubiquinol to molecular oxygen. In this study, mutants lacking either of these terminal oxidases were characterized. Deletion of the cydAB genes for cytochrome bd had no obvious influence on growth, whereas the lack of the cyoBACD genes for cytochrome bo3 severely reduced the growth rate and the cell yield. Using a respiration activity monitoring system and adjusting different levels of oxygen availability, hints for a low oxygen affinity of cytochrome bd oxidase were obtained, which were supported by measurements of oxygen consumption in a respirometer. The H+/O ratio of the M-NM-^TcyoBACD mutant with mannitol as substrate was 0.56 M-BM-1 0.11 and more than 50% lower than that of the reference strain (1.26 M-BM-1 0.06) and the delta-cydAB mutant (1.31 M-BM-1 0.16), indicating that cytochrome bo3 oxidase is the main component for proton extrusion via the respiratory chain. Plasmid-based overexpression of cyoBACD led to increased growth rates and growth yields, both in the wild type and the delta-cyoBACD mutant, suggesting that cytochrome bo3 might be the rate-limiting factor of the respiratory chain. The three transcriptome comparisons of G. oxydans M-NM-^TuppM-NM-^TcyoBACD vs. G.oxydans M-NM-^Tupp were repeated independently three times in biological replicates resulting in 3 hybridizations as termed by sample 1 to 3.
2013-07-26 | E-GEOD-47782 | biostudies-arrayexpress
Project description:Carbon monoxide (CO) is a gas infamous for its acute toxicity. The toxicity of CO predominately stems from its tendency to form carbonyl complexes with transition metals, thus inhibiting the heme-prosthetic groups of proteins, including the terminal oxidases of the respiratory chain. While CO has been proposed as an antibacterial agent, the evidence supporting its toxicity towards bacteria is equivocal, and its cellular targets remain poorly defined. In this work, we investigate the physiological response of Mycobacterium smegmatis to CO. We show that M. smegmatis is highly resistant to the toxic effects of CO, exhibiting normal growth parameters when cultured in its presence. We profiled the proteome of M. smegmatis during growth in CO, identifying strong induction of cytochrome bd oxidase and members of the dos regulon, but relatively few other changes. We show that the activity of cytochrome bd oxidase is resistant to CO, whereas cytochrome bcc-aa3 oxidase is strongly inhibited by this gas. Consistent with these findings, growth analysis shows that M. smegmatis lacking cytochrome bd oxidase displays a significant growth defect in the presence of CO, while induction of the dos regulon appears to be unimportant for adaption to CO. Altogether, our findings suggest that M. smegmatis has considerable resistance to CO and benefits from respiratory flexibility to withstand its inhibitory effects.
2021-04-30 | PXD018382 | Pride
Project description:Cytochrome c oxidase barcodes for aquatic oligochaete identification: development of a Swiss reference database
| PRJEB21713 | ENA
Project description:Mycobacterial energy metabolism currently attracts strong attention as new target space for development of anti-tuberculosis drugs. The imidazopyridine Q203 targets the cytochrome bcc complex of the respiratory chain, a key component in energy metabolism. Q203 blocks growth of Mycobacterium tuberculosis at nanomolar concentrations, however, it fails to actually kill the bacteria, which may limit the clinical applicability of this candidate drug. In this report we show that inhibition of cytochrome bd, a parallel branch of the mycobacterial respiratory chain, by aurachin D invoked bactericidal activity of Q203. In biochemical assays using inverted membrane vesicles from Mycobacterium tuberculosis and Mycobacterium smegmatis we found that inhibition of respiratory chain activity by Q203 was incomplete, but could be enhanced by inactivation of cytochrome bd, either by genetic knock-out or by inhibition with aurachin D. These results indicate that simultaneously targeting the cytochrome bcc and the cytochrome bd branch of the mycobacterial respiratory chain may turn out as effective strategy for combating M. tuberculosis.
| S-EPMC5805707 | biostudies-literature
Project description:We report here lead optimisation efforts for molecule GW861072X, one of 177 leads published in a GSK-led phenotypic screening campaign by Balell et al. (2013), generating the AX series. Along with the parent compound AX-35, four other derivatives with mild to no cytotoxicity showed potent in vitro and ex vivo activity in infected THP-1 macrophages against M. tuberculosis. Isolation of resistant mutants to AX compounds in M. tuberculosis revealed mutations in the QcrB of the cytochrome bc1 oxidase, one of two terminal oxidases of the mycobacterial electron transport chain. Cross-resistance studies, transcriptomic analyses and bioenergetics flux assays provide further evidence of QcrB as the target of the AX compounds, and that AX compounds likely interact differently with the quinol binding pocket compared to other QcrB inhibitors. The transcriptomic and bioenergetic profiles obtained when M. tuberculosis was treated with AX-35 are similar to transcriptomic and respiratory signatures of other cytochrome bc1 oxidase inhibitors, whereby the pronounced role of the alternate terminal oxidase cytochrome bd in the respiratory adaptation of M. tuberculosis could be observed. Genes involved in utilisation and synthesis of triacylglycerol (TAG) were also additionally observed to be up-regulated with AX treatment, indicating a switch induced towards lipid metabolism under this particular stress.
2018-04-26 | GSE113683 | GEO
Project description:We previously determined that loss of respiratory quinol oxidase cytochrome bd disrupts biofilm formation in uropathogenic Escherichia coli (UPEC). In this study, we extracted and interrogated the outer membrane and extracellular matrix of colony biofilms formed by UPEC isolate UTI89 and an isogenic mutant lacking cytochrome bd (∆cydAB).
2021-04-01 | PXD023998 | Pride
Project description:Cytochrome bd (CydAB), a high-affinity oxidase that performs terminal oxygen reduction in cellular respiration, is used by various bacteria to grow in hypoxic environments, form nonreplicating persister cells, or resist antimicrobial killing. It is thought that oxygen concentration solely determines the usage of CydAB in bacteria, with the tradeoff being that CydAB-containing respiratory chains generate less ATP than those containing low-affinity proton-pumping cytochrome oxidases, as CydAB does not pump protons when generating a proton motive force (PMF). However, CydAB has roles in acid, nitrosative and oxidative stress that suggest the existence of oxygen-independent CydAB usage. Here, we show that an obligate aerobe, the soil actinomycete Mycobacterium smegmatis, uses CydAB to normoxically maintain a homeostatic balance of the PMF, involving an oxygen-independent interaction with the classical hypoxia regulator (DosR). We show that overpotentials of the PMF apply feedback inhibition on the proton-pumping, low-affinity, cytochrome c oxidase supercomplex bcc-aa3, and that CydAB can immediately escape this inhibition and promote a PMF-responsive programme.
2023-02-28 | GSE167408 | GEO
Project description:We report here lead optimisation efforts of a new series of cytochrome bc1 oxidase inhibitors, the quinazoline derivatives. Four derivatives showed mild to no cytotoxicity as potent in vitro and ex vivo activity in infected THP-1 macrophages against M. tuberculosis. Isolation of resistant mutants to one of the derivatives in M. tuberculosis revealed mutations in both QcrA and QcrB of the cytochrome bc1 oxidase, one of two terminal oxidases of the mycobacterial electron transport chain. Cross-resistance studies, transcriptomic analyses and bioenergetics flux assays provide further evidence of the cytochrome bc1 as the target of the quinazolines compounds. The transcriptomic and bioenergetic profiles obtained when M. tuberculosis was treated with 11626252 are similar to transcriptomic and respiratory signatures of other cytochrome bc1 oxidase inhibitors.
2019-08-01 | GSE119158 | GEO