Overcoming Mycobacterium tuberculosis through small molecule inhibitors to break down cell wall synthesis

Kuang, Wenbin; Zhang, Haolin; Wang, Xiao; Yang, Peng

doi:10.1016/j.apsb.2022.04.014

Cited by 13 publications

(10 citation statements)

References 99 publications

(105 reference statements)

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“…Atypical among bacteria, it has an elaborate dense multilayered structure, devoid of the majority of transporters, that helps to protect it against the actions of the host immune cells, adverse environments, and many antimicrobial agents. It is thus not surprising that various inhibitors of specific processes of the cell wall biosynthesis [ 8 , 9 , 10 , 11 ] have long been established as a major group of antitubercular drugs. Moreover, the approaches aiming to directly target and modulate the mycobacterial membranes are currently seen as very promising [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Conformational Dynamics and Stability of Bilayers Formed by Mycolic Acids from the Mycobacterium tuberculosis Outer Membrane

et al. 2023

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Bilayers of mycolic acids (MAs) form the outer membrane of Mycobacterium tuberculosis that has high strength and extremely low permeability for external molecules (including antibiotics). For the first time, we were able to study them using the all-atom long-term molecular dynamic simulations (from 300 ns up to 1.2 μs) in order to investigate the conformational changes and most favorable structures of the mycobacterial membranes. The structure and properties of the membranes are crucially dependent on the initial packing of the α-mycolic acid (AMA) molecules, as well as on the presence of the secondary membrane components, keto- and methoxy mycolic acids (KMAs and MMAs). In the case of AMA-based membranes, the most labile conformation is W while other types of conformations (sU as well as sZ, eU, and eZ) are much more stable. In the multicomponent membranes, the presence of the KMA and MMA components (in the W conformation) additionally stabilizes both the W and eU conformations of AMA. The membrane in which AMA prevails in the eU conformation is much thicker and, at the same time, much denser. Such a packing of the MA molecules promotes the formation of a significantly stronger outer mycobacterial membrane that should be much more resistant to the threatening external factors.

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Section: Introductionmentioning

confidence: 99%

Conformational Dynamics and Stability of Bilayers Formed by Mycolic Acids from the Mycobacterium tuberculosis Outer Membrane

et al. 2023

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“…Numerous studies suggest that the pathogenesis and durability of mycolic acids depend on the functional groups in their acyl chains [50]. The 1KPI proteins various metabolic activities are inhibited by a few nitrogen containing heterocyclic drug molecules [51]. Hence, we chosen the 1KPI protein for docking studies with the synthesized compounds.…”

Section: Methodsmentioning

confidence: 99%

An eco‐efficient new path of mortar pestle grinding approach for the construction of methanol and ethylthio substituted pyridines with in silico studies

Edapu,

Boodida,

Pagadala

et al. 2023

Journal of Heterocyclic Chem

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A green and highly regioselective approach for the synthesis of poly‐substituted new pyridine derivatives via the Knoevenagel condensation followed by the Michael addition. The reaction involves intramolecular cyclization of easily obtainable reactants under environmentally and economically benign mortar pestle grinding technique. This method clearly proves that spatially hindered aldehydes also actively contribute to the construction of the desired pyridine derivatives with good yield (85%–96%) in about 30–40 min. This new avenue offers a number of benefits over earlier reaction approaches such as lengthy work‐up‐processes, operational difficulties and lower yields. This mortar pestle grinding technique is familiar for environmental and economical benign protocols. The druggability properties of synthesized compounds assessed using in silico studies.

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“…The EmbC is a transmembrane protein that plays a crucial role in extending the arabinan chains in AG and LAM 13 . Ethambutol (EMB), a first-line anti-tuberculosis drug, can mediate the addition of arabinose units to the growing polysaccharide chains, thereby determining the length and structure of the arabinan 14 . Inhibition of arabinan synthesis eliminates the mycolic acid anchoring site, causing a reduction in the accumulation of mycolic acids in the cell wall.…”

Section: Introductionmentioning

confidence: 99%

EmbB and EmbC Regulate the Sensitivity ofMycobacterium abscessusto Echinomycin

He,

Gao,

Wang

et al. 2024

Preprint

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Treatment ofMycobacterium abscessus(Mab) infection is a major challenge due to its intrinsic resistance to most available drugs. It is thus imperative to find new anti-Mab drugs. In this study, we investigated the activity and intrinsic resistance mechanism of echinomycin (ECH) against Mab. ECH is active against Mab (MIC: 2 µg/mL). TheembCgene knockout strain (MabΔembC) showed hyper-sensitive to ECH (MIC: 0.0078-0.0156 µg/mL). The MICs of ECH-resistant strains screened based on the MabΔembCstrain were 0.25-1 µg/mL. Mutations were found in the EmbB, including Asp306Ala, Asp306Asn, Arg350Gly, Val555Ile, and Gly581Ser, which led to increased resistance to ECH when overexpressed in MabΔembCindividually (0.25-0.5 µg/mL). The EmbB mutants edited by the CRISPR/Cpf1 system became more resistant to ECH (MIC: 0.25-0.5 µg/mL). The permeability of gene-edited and overexpressed Mab strains was reduced, as shown by the ethidium bromide accumulation assay, but it was still significantly higher than that of the parent Mab. To summarize, our study demonstrates that ECH has a strong anti-Mab activity and confirms that EmbB and EmbC are related to the sensitivity of Mab to ECH. EmbB mutation may partially compensate for the function of EmbC.Impact StatementMycobacterium abscessus(Mab) is a rapidly growing, intrinsic multidrug-resistant Mycobacterium. This study demonstrated that echinomycin (ECH) has potent antibacterial activity against Mab, and the mechanism of ECH resistance to Mab is related to EmbB and EmbC. EmbB and EmbC can alter the sensitivity of Mab to ECH by altering the permeability of its cell wall. In addition, there is a functional complementary evolution between EmbB and EmbC to regulate sensitivity to ECH. Overall, our study provides a novel anti-Mab drug candidate ECH and a scientific foundation for developing effective strategies to prevent and control Mab.

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Overcoming Mycobacterium tuberculosis through small molecule inhibitors to break down cell wall synthesis

Cited by 13 publications

References 99 publications

Conformational Dynamics and Stability of Bilayers Formed by Mycolic Acids from the Mycobacterium tuberculosis Outer Membrane

Conformational Dynamics and Stability of Bilayers Formed by Mycolic Acids from the Mycobacterium tuberculosis Outer Membrane

An eco‐efficient new path of mortar pestle grinding approach for the construction of methanol and ethylthio substituted pyridines with in silico studies

EmbB and EmbC Regulate the Sensitivity ofMycobacterium abscessusto Echinomycin

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