Targeting the cytochrome bc1 complex for drug development in M. tuberculosis: review

Wani, Mushtaq Ahmad; Dhaked, Devendra K.

doi:10.1007/s11030-021-10335-y

Cited by 7 publications

(8 citation statements)

References 127 publications

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“…The energy released in this process is conserved by proton-pumping transmembrane proteins that establish a proton gradient and thus generate an electrochemical gradient, called proton motive force (PMF). This bioenergetic pathway generates ATP from the phosphorylation of ADP [ 57 , 58 ].…”

Section: Emerging Mtb Drug Targetsmentioning

confidence: 99%

“…However, cyt bc 1 -aa 3 is not essential for cell survival and as long as the alternate cyt bd is expressed, bc 1 -aa 3 inhibitors do not induce bactericidal effects. The central role of the bc 1 -aa 3 complex in the ETC and the significant differences to the mammalian counterpart make the supercomplex a good therapeutical target [ 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ].…”

Section: Emerging Mtb Drug Targetsmentioning

confidence: 99%

“…Thus, in order to address its shortcomings, a medicinal chemistry approach was conducted to study the chemical space of diarylquinolines to find next-generation equivalents with superior safety profiles. In this context, two 3,5-diakoxy-4-pyridyl derivatives, TBAJ-587 and TBAJ-876 ( Figure 4 C), were found to be particularly interesting and are currently in phase I clinical trials [ 58 , 61 , 68 , 77 ].…”

Section: Emerging Mtb Drug Targetsmentioning

confidence: 99%

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Target Identification in Anti-Tuberculosis Drug Discovery

Capela

Félix

Clariano

et al. 2023

IJMS

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Mycobacterium tuberculosis (Mtb) is the etiological agent of tuberculosis (TB), a disease that, although preventable and curable, remains a global epidemic due to the emergence of resistance and a latent form responsible for a long period of treatment. Drug discovery in TB is a challenging task due to the heterogeneity of the disease, the emergence of resistance, and uncomplete knowledge of the pathophysiology of the disease. The limited permeability of the cell wall and the presence of multiple efflux pumps remain a major barrier to achieve effective intracellular drug accumulation. While the complete genome sequence of Mtb has been determined and several potential protein targets have been validated, the lack of adequate models for in vitro and in vivo studies is a limiting factor in TB drug discovery programs. In current therapeutic regimens, less than 0.5% of bacterial proteins are targeted during the biosynthesis of the cell wall and the energetic metabolism of two of the most important processes exploited for TB chemotherapeutics. This review provides an overview on the current challenges in TB drug discovery and emerging Mtb druggable proteins, and explains how chemical probes for protein profiling enabled the identification of new targets and biomarkers, paving the way to disruptive therapeutic regimens and diagnostic tools.

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Section: Emerging Mtb Drug Targetsmentioning

confidence: 99%

Section: Emerging Mtb Drug Targetsmentioning

confidence: 99%

Section: Emerging Mtb Drug Targetsmentioning

confidence: 99%

See 1 more Smart Citation

Target Identification in Anti-Tuberculosis Drug Discovery

Capela

Félix

Clariano

et al. 2023

IJMS

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show abstract

“…The energy released in this process is conserved by protonpumping transmembrane proteins that establish a proton gradient and thus generate an electrochemical gradient, called proton motive force (PMF). This bioenergetic pathway generates ATP from the phosphorylation of ADP [57,58].…”

Section: Energy Metabolismmentioning

confidence: 99%

Target Identification in Anti-tuberculosis Drug Discovery

Capela¹,

Félix²,

Clariano³

et al. 2023

Preprint

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Mycobacterium tuberculosis (Mtb) is the etiological agent of tuberculosis (TB), a disease that alt-hough preventable and curable, remains a global epidemic due to the emergence of resistance and a latent form responsible for a long period of treatment. Drug discovery in TB is a challenging task due to the heterogeneity of the disease, the emergence of resistance and an uncomplete knowledge of the pathophysiology of the disease. The limited permeability of the cell wall and the presence of multiple efflux pumps remain a major barrier to achieve effective intracellular drug accumulation. While the complete genome sequence of Mtb has been determined and several potential protein targets have been validated, the lack of adequate models for in vitro and in vivo studies is a limit-ing factor in TB drug discovery programs. In current therapeutic regimens, less than 0.5% of bac-terial proteins are targeted being the biosynthesis of the cell wall and the energetic metabolism two of the most important processes exploited for TB chemotherapeutics. This review provides an overview on the current challenges in TB drug discovery and emerging Mtb druggable proteins, and how chemical probes for protein profiling enabled the identification of new targets and bi-omarkers, paving the way to disruptive therapeutic regimens and diagnostic tools.

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“…The M. tuberculosis electron transport chain has recently gained interest as a target space for next-generation antibacterials [ 91 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 ]. M. tuberculosis possesses a branched aerobic respiratory chain.…”

Section: Cytochrome Bd As a Prospective Target For...mentioning

confidence: 99%

Recent Advances in Structural Studies of Cytochrome bd and Its Potential Application as a Drug Target

Friedrich

Wohlwend

Borisov

2022

IJMS

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Cytochrome bd is a triheme copper-free terminal oxidase in membrane respiratory chains of prokaryotes. This unique molecular machine couples electron transfer from quinol to O2 with the generation of a proton motive force without proton pumping. Apart from energy conservation, the bd enzyme plays an additional key role in the microbial cell, being involved in the response to different environmental stressors. Cytochrome bd promotes virulence in a number of pathogenic species that makes it a suitable molecular drug target candidate. This review focuses on recent advances in understanding the structure of cytochrome bd and the development of its selective inhibitors.

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Targeting the cytochrome bc1 complex for drug development in M. tuberculosis: review

Cited by 7 publications

References 127 publications

Target Identification in Anti-Tuberculosis Drug Discovery

Target Identification in Anti-Tuberculosis Drug Discovery

Target Identification in Anti-tuberculosis Drug Discovery

Recent Advances in Structural Studies of Cytochrome bd and Its Potential Application as a Drug Target

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