Suramin is a potent and selective inhibitor of Mycobacterium tuberculosis RecA protein and the SOS response: RecA as a potential target for antibacterial drug discovery

ABSTRACTOne way to speed up the TB drug discovery process is to search for antitubercular activity among compound series that already possess some of the key properties needed in anti-infective drug discovery, such as whole-cell activity and oral absorption. Here, we present MGIs, a new series ofMycobacterium tuberculosisgyrase inhibitors, which stem from the long-term efforts GSK has dedicated to the discovery and development of novel bacterial topoisomerase inhibitors (NBTIs). The compounds identified were found to be devoid of fluoroquinolone (FQ) cross-resistance and seem to operate through a mechanism similar to that of the previously described NBTI GSK antibacterial drug candidate. The remarkablein vitroandin vivoantitubercular profiles showed by the hits has prompted us to further advance the MGI project to full lead optimization.

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Structural analysis of protein translocase subunit SecY from Mycobacterium tuberculosis H37Rv: a potential target for anti-tuberculosis drug discovery

International Journal of Computational Biology and Drug Design ◽

10.1504/ijcbdd.2017.088137 ◽

2017 ◽

Vol 10 (4) ◽

pp. 374

Author(s):

Tilahun Melak Sitote ◽

Sunita Gakkhar

Keyword(s):

Mycobacterium Tuberculosis ◽

Drug Discovery ◽

Structural Analysis ◽

Tuberculosis H37rv ◽

Mycobacterium Tuberculosis H37rv ◽

Potential Target

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Crystal structure of Mycobacterium tuberculosis ketol-acid reductoisomerase at 1.0 Å resolution - a potential target for anti-tuberculosis drug discovery

FEBS Journal ◽

10.1111/febs.13672 ◽

2016 ◽

Vol 283 (7) ◽

pp. 1184-1196 ◽

Cited By ~ 19

Author(s):

You Lv ◽

Ajit Kandale ◽

Shun Jie Wun ◽

Ross P. McGeary ◽

Simon J. Williams ◽

...

Keyword(s):

Crystal Structure ◽

Mycobacterium Tuberculosis ◽

Drug Discovery ◽

Potential Target

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In silico structure-based design of a novel class of potent and selective small peptide inhibitor of Mycobacterium tuberculosis Dihydrofolate reductase, a potential target for anti-TB drug discovery

Molecular Diversity ◽

10.1007/s11030-009-9172-6 ◽

2009 ◽

Vol 14 (3) ◽

pp. 595-604 ◽

Cited By ~ 25

Author(s):

Manoj Kumar ◽

Rajakrishnan Vijayakrishnan ◽

Gita Subba Rao

Keyword(s):

Mycobacterium Tuberculosis ◽

Drug Discovery ◽

Dihydrofolate Reductase ◽

In Silico ◽

Peptide Inhibitor ◽

Small Peptide ◽

Potential Target

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Moxifloxacin Activates the SOS Response in Mycobacterium tuberculosis in a Dose- and Time-Dependent Manner

Microorganisms ◽

10.3390/microorganisms9020255 ◽

2021 ◽

Vol 9 (2) ◽

pp. 255

Author(s):

Angelo Iacobino ◽

Giovanni Piccaro ◽

Manuela Pardini ◽

Lanfranco Fattorini ◽

Federico Giannoni

Keyword(s):

Gene Expression ◽

Mycobacterium Tuberculosis ◽

Physiological State ◽

Transcriptional Response ◽

Sos Response ◽

Resistant Mutant ◽

Time Dependent ◽

Dependent Manner ◽

Gyra Gene ◽

Drug Concentrations

Previous studies on Escherichia coli demonstrated that sub-minimum inhibitory concentration (MIC) of fluoroquinolones induced the SOS response, increasing drug tolerance. We characterized the transcriptional response to moxifloxacin in Mycobacterium tuberculosis. Reference strain H37Rv was treated with moxifloxacin and gene expression studied by qRT-PCR. Five SOS regulon genes, recA, lexA, dnaE2, Rv3074 and Rv3776, were induced in a dose- and time-dependent manner. A range of moxifloxacin concentrations induced recA, with a peak observed at 2 × MIC (0.25 μg/mL) after 16 h. Another seven SOS responses and three DNA repair genes were significantly induced by moxifloxacin. Induction of recA by moxifloxacin was higher in log-phase than in early- and stationary-phase cells, and absent in dormant bacilli. Furthermore, in an H37Rv fluoroquinolone-resistant mutant carrying the D94G mutation in the gyrA gene, the SOS response was induced at drug concentrations higher than the mutant MIC value. The 2 × MIC of moxifloxacin determined no significant changes in gene expression in a panel of 32 genes, except for up-regulation of the relK toxin and of Rv3290c and Rv2517c, two persistence-related genes. Overall, our data show that activation of the SOS response by moxifloxacin, a likely link to increased mutation rate and persister formation, is time, dose, physiological state and, possibly, MIC dependent.

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High-resolution structures of inhibitor complexes of human indoleamine 2,3-dioxygenase 1 in a new crystal form

Acta Crystallographica Section F Structural Biology Communications ◽

10.1107/s2053230x18012955 ◽

2018 ◽

Vol 74 (11) ◽

pp. 717-724 ◽

Cited By ~ 10

Author(s):

Shukun Luo ◽

Ke Xu ◽

Shaoyun Xiang ◽

Jie Chen ◽

Chunyun Chen ◽

...

Keyword(s):

Drug Discovery ◽

High Resolution ◽

Crystal Structures ◽

Active Site ◽

Crystal Form ◽

Crystal Forms ◽

Cellular Processes ◽

Potential Target ◽

Indoleamine 2,3 Dioxygenase

Human indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-dependent enzyme with important roles in many cellular processes and is a potential target for drug discovery against cancer and other diseases. Crystal structures of IDO1 in complex with various inhibitors have been reported. Many of these crystals belong to the same crystal form and most of the reported structures have resolutions in the range 3.2–2.3 Å. Here, three new crystal forms of human IDO1 obtained by introducing a surface mutation, K116A/K117A, distant from the active site are reported. One of these crystal forms diffracted to 1.5 Å resolution and can be readily used for soaking experiments to determine high-resolution structures of IDO1 in complex with the substrate tryptophan or inhibitors that coordinate the heme. In addition, this mutant was used to produce crystals of a complex with an inhibitor that targets the apo form of the enzyme under the same conditions; the structure of this complex was determined at 1.7 Å resolution. Overall, this mutant represents a robust platform for determining the structures of inhibitor and substrate complexes of IDO1 at high resolution.

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