Cell Wall Associated Factors of Mycobacterium tuberculosis as Major Virulence Determinants: Current Perspectives in Drugs Discovery and Design

Singh, Gurdyal; Kumar, Arbind; Maan, Pratibha; Kaur, Jagdeep

doi:10.2174/1389450118666170711150034

Cited by 17 publications

(9 citation statements)

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“…Lipid profiling studies showed increase in total lipid and TDM content in rv1288 expressing M. smegmatis strain. Virulent M.tb strains are usually rich in TDM (Singh et al, 2017). Similarly the expression of mycolyl transferase Ag85A protein in M. smegmatis resulted in increase concentration of the glycolipids TDM and TMM in the cell (Elamin et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Rv1288, a Two Domain, Cell Wall Anchored, Nutrient Stress Inducible Carboxyl-Esterase of Mycobacterium tuberculosis, Modulates Cell Wall Lipid

Maan

Kumar

Kaur

2018

Front. Cell. Infect. Microbiol.

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Rv1288, a conserved hypothetical protein of M. tuberculosis (M.tb), was recently characterized as two-domain esterase enzyme by in silico study. In the present study, Rv1288 and its domains (Est and Lyt) were cloned individually from M.tb into E. coli for expression and purification. The purified rRv1288 and rEst proteins exhibited lipolytic activity with medium chain length esters as optimum substrates, while Lyt domain did not show enzymatic activity. However, presence of Lyt domain resulted in enhanced rate of protein aggregation at higher temperature. Both rRv1288 and rEst followed the similar patterns of substrate specificity, temperature and pH activity. Site directed mutagenesis confirmed the Ser-294, Asp-391 and His-425 as catalytic site residues. Rv1288 was found to be present in cell wall fraction of M.tb H37Ra. Peptidoglycan binding activity of Rv1288 and its domains demonstrated that the Lyt domain is essential for anchoring protein to the cell wall. Expression of rv1288 was up regulated in M.tb under nutrient starved condition. Over expression of rv1288 in surrogate host M. smegmatis led to change in colony morphology, enhanced pellicle and aggregate formation that might be linked with the changed lipid composition of bacterial cell wall. Cell wall of M. smegmatis expressing rv1288 had higher amount of lipids, with a significant increase in trehalose dimycolate content. Rv1288 also leads to increase in drug resistance of M. smegmatis. Rv1288 also enhanced the intracellular survival of M. smegmatis in Raw264.7 cell line. Overall, this study suggested that Rv1288, a cell wall localized carboxyl hydrolase with mycolyl-transferase activity, modulated the cell wall lipids to favor the survival of bacteria under stress condition.

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Section: Discussionmentioning

confidence: 99%

Rv1288, a Two Domain, Cell Wall Anchored, Nutrient Stress Inducible Carboxyl-Esterase of Mycobacterium tuberculosis, Modulates Cell Wall Lipid

Maan

Kumar

Kaur

2018

Front. Cell. Infect. Microbiol.

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“…Most of bacteria have a protective outer shell (cell wall), and Mab's low permeability cell wall plays a vital role in their intrinsic resistance 25 .…”

Section: Discussionmentioning

confidence: 99%

“…Most of bacteria have a protective outer shell (cell wall), and Mab’s low permeability cell wall plays a vital role in their intrinsic resistance 25 . Arabinosyltransferase C, a protein involved in cell wall synthesis, is encoded by the embC gene, and the impairment of cell wall synthesis caused by the loss of embC increases the permeability of the cell wall in Mab, making the bacteria more sensitive to antibiotics 19, 26 .…”

Section: Discussionmentioning

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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“…Plasma membrane also contains lipoglycans, phospholipids including phosphatidylinositol mannosides, and other glycolipids [11]. Antigen 85 complex proteins, porins, putative transporters, and mammalian cell entry protein family were mostly found in mycobacterial cell wall fraction that contains mycolic acid esterifying arabinogalactan constituting the inner leaflet of mycomembrane, along with glycolipids, phospholipids, lipoglycans, and proteins [12].…”

Section: Components Of Mycobacterial Cell Wallmentioning

confidence: 99%

An Exhaustive Review on Emerging Drug Targets of Tuberculosis With Special Emphasis on Cell Wall Synthesis

Thakar

Bansode

2021

Innovare J Life Sci

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Tuberculosis (TB) is one of the top 10 causes of mortality and morbidity. Worldwide, yet, it has been over 60 years since a novel drug was introduced in market to treat the disease exclusively. Increased number of drug resistant TB cases has prompted the search for novel potent anti-TB drug. Mycobacterial cell wall has unique structure which provides integrity to the cell. The future development of new potent anti-TB drug targets is associated with the synthesis of various cell wall constituents; the structural and genetic information about mycobacterial cell wall envelope is now available. In the present review, we have focused on prospective drug targets that can be optimum triumph for successful drug candidate.

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Cell Wall Associated Factors of Mycobacterium tuberculosis as Major Virulence Determinants: Current Perspectives in Drugs Discovery and Design

Cited by 17 publications

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Rv1288, a Two Domain, Cell Wall Anchored, Nutrient Stress Inducible Carboxyl-Esterase of Mycobacterium tuberculosis, Modulates Cell Wall Lipid

Rv1288, a Two Domain, Cell Wall Anchored, Nutrient Stress Inducible Carboxyl-Esterase of Mycobacterium tuberculosis, Modulates Cell Wall Lipid

EmbB and EmbC Regulate the Sensitivity ofMycobacterium abscessusto Echinomycin

An Exhaustive Review on Emerging Drug Targets of Tuberculosis With Special Emphasis on Cell Wall Synthesis

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