Molecular Modelling and Atomistic Insights into the Binding Mechanism of MmpL3 <i>Mtb</i>

Kwofie, Samuel K.; Hanson, George W.; Sasu, Henrietta; Enninful, Kweku S.; Mensah, Francis A.; Nortey, Richmond T.; Yeboah, Omane P.; Agoni, Clement; Wilson, Michael D.

doi:10.1002/cbdv.202200160

Cited by 5 publications

(3 citation statements)

References 39 publications

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“…Other promising MmpL3 inhibitors include indolocarboxamides and adamantylureas. As part of a drug scaffold repurposing program, the cannabinoid receptor modulator rimonabant (Figure 2B) and its diaryl pyrazole analogs were reported to display potent anti-TB activity [45,46]. Arabinogalactan polysaccharide layer.…”

Section: Cell Wallmentioning

confidence: 99%

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: Cell Wallmentioning

confidence: 99%

Target Identification in Anti-Tuberculosis Drug Discovery

Capela

Félix

Clariano

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…Other promising MmpL3 inhibitors include indolocarboxamides and adamantylureas. As part of a drug scaffold repurposing program, the cannabinoid receptor modulator rimonabant (Figure 2B) and its diaryl pyrazole analogs, was reported to display potent anti-TB activity [45,46]. Arabinogalactan polysaccharide layer.…”

Section: Cell Wallmentioning

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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“…Mycobacteria possess a remarkably complex cell envelope consisting of a cytoplasmic membrane and a cell wall, constituting an efficient permeability barrier, which plays a crucial role in intrinsic drug resistance and survival under harsh conditions [7]. Mycobacterium smegmatis (Ms) MmpL3 mutant strains exhibit alterations in cell wall hydrophobicity and growth defects, resulting in resistance to two anti-tubercular agents, SQ109 and AU1235 [8]. The previous study reported that the Rv2686c-Rv2687c-Rv2688c operon, which encodes an ABC transporter in Mtb, conferred Ms resistance to ciprofloxacin [9].…”

Section: Introductionmentioning

confidence: 99%

Impact of MSMEG5257 Deletion on Mycolicibacterium smegmatis Growth

He,

Zhao,

et al. 2024

Microorganisms

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Mycobacterial membrane proteins play a pivotal role in the bacterial invasion of host cells; however, the precise mechanisms underlying certain membrane proteins remain elusive. Mycolicibacterium smegmatis (Ms) msmeg5257 is a hemolysin III family protein that is homologous to Mycobacterium tuberculosis (Mtb) Rv1085c, but it has an unclear function in growth. To address this issue, we utilized the CRISPR/Cas9 gene editor to construct Δmsmeg5257 strains and combined RNA transcription and LC-MS/MS protein profiling to determine the functional role of msmeg5257 in Ms growth. The correlative analysis showed that the deletion of msmeg5257 inhibits ABC transporters in the cytomembrane and inhibits the biosynthesis of amino acids in the cell wall. Corresponding to these results, we confirmed that MSMEG5257 localizes in the cytomembrane via subcellular fractionation and also plays a role in facilitating the transport of iron ions in environments with low iron levels. Our data provide insights that msmeg5257 plays a role in maintaining Ms metabolic homeostasis, and the deletion of msmeg5257 significantly impacts the growth rate of Ms. Furthermore, msmeg5257, a promising drug target, offers a direction for the development of novel therapeutic strategies against mycobacterial diseases.

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Molecular Modelling and Atomistic Insights into the Binding Mechanism of MmpL3 Mtb

Cited by 5 publications

References 39 publications

Target Identification in Anti-Tuberculosis Drug Discovery

Target Identification in Anti-Tuberculosis Drug Discovery

Target Identification in Anti-tuberculosis Drug Discovery

Impact of MSMEG5257 Deletion on Mycolicibacterium smegmatis Growth

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