Tanya Parish

Infectious Disease Research Institute

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Neil G. Stoker

University College London

Aaron Korkegian

Infectious Disease Research Institute

Amanda C. Brown

Texas A&M University

Joshua Odingo

Infectious Disease Research Institute

Yulia Ovechkina

Infectious Disease Research Institute

Julie V. Early

Infectious Disease Research Institute

Mai A. Bailey

Infectious Disease Research Institute

Juliane Ollinger

Infectious Disease Research Institute

Torey Alling

LAC+USC Medical Center

Matthew B. McNeil

Maurice Wilkins Centre

Cooperative Institutions

Infectious Disease Research Institute

Colorado State University

Centre National de la Recherche Scientifique

University of London

Harvard University

Queen Mary University of London

Cornell University

University of Cape Town

University of Dundee

University of Illinois Chicago

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

How Mycobacterium tuberculosis drug resistance has shaped anti-tubercular drug discovery

Frontiers in Cellular and Infection Microbiology (2022)

Amala Bhagwat Aditi Deshpande Tanya Parish

Drug resistance is an increasing problem for the treatment of tuberculosis. The prevalence of clinical isolates with pre-existing resistance needs to be considered in any drug discovery program. Non-specific mechanisms of resistance such as increased efflux or decreased permeability need to be considered both in developing individual drug candidates and when designing novel regimens. We review a number of different approaches to develop new analogs and drug combinations or improve efficacy of existing drugs that may overcome or delay the appearance of clinical resistance. We also discuss the need to fully characterize mechanisms of resistance and cross- resistance to existing drugs to ensure that novel drugs will be clinically effective.

Efflux

10.3389/fcimb.2022.974101

Cite

Citations (8)

Novel C-3-(N-alkyl-aryl)-aminomethyl rifamycin SV derivatives exhibit activity against rifampicin-resistant Mycobacterium tuberculosis RpoBS522L strain and display a different binding mode at the RNAP β-subunit site compared to rifampicin

European Journal of Medicinal Chemistry (2021)

Mire Zloh Megha Gupta Tanya Parish Federico Brucoli

Rifamycin

10.1016/j.ejmech.2021.113734

Cite

Citations (4)

Identification of Phenoxyalkylbenzimidazoles with Antitubercular Activity

Journal of Medicinal Chemistry (2015)

N. Susantha Chandrasekera Torey Alling Mai A. Bailey Megan Files Julie V. Early

We conducted an evaluation of the phenoxyalkylbenzimidazole series based on the exemplar 2-ethyl-1-(3-phenoxypropyl)-1H-benzo[d]imidazole for its antitubercular activity. Four segments of the molecule were examined systematically to define a structure-activity relationship with respect to biological activity. Compounds had submicromolar activity against Mycobacterium tuberculosis; the most potent compound had a minimum inhibitory concentration (MIC) of 52 nM and was not cytotoxic against eukaryotic cells (selectivity index = 523). Compounds were selective for M. tuberculosis over other bacterial species, including the closely related Mycobacterium smegmatis. Compounds had a bacteriostatic effect against aerobically grown, replicating M. tuberculosis, but were bactericidal against nonreplicating bacteria. Representative compounds had moderate to high permeability in MDCK cells, but were rapidly metabolized in rodents and human liver microsomes, suggesting the possibility of rapid in vivo hepatic clearance mediated by oxidative metabolism. These results indicate that the readily synthesized phenoxyalkylbenzimidazoles are a promising class of potent and selective antitubercular agents, if the metabolic liability can be solved.

Identification

10.1021/acs.jmedchem.5b00546

Cite

Citations (41)

An inducible expression system permitting the efficient purification of a recombinant antigen fromMycobacterium smegmatis

FEMS Microbiology Letters (1998)

James A. Triccas Tanya Parish Warwick J. Britton Brigitte Gicquel

A novel expression vector utilising the highly inducible acetamidase promoter of Mycobacterium smegmatis was constructed. High-level induction of a model antigen, the Mycobacterium leprae 35 kDa protein, was demonstrated in recombinant M. smegmatis grown in the presence of the acetamidase inducer acetamide. The recombinant protein could be simply and efficiently purified from the bacterial sonicate by virtue of a C-terminal 6-histidine tag, demonstrating that this purification strategy can be used for the mycobacteria. The histidine tag had no apparent effect on the protein conformation or immunogenicity, suggesting that the vector described may prove useful for the purification of native-like recombinant mycobacterial proteins from fast-growing mycobacterial hosts.

Mycobacterium smegmatis

FLAG-tag

Mycobacterium leprae

10.1111/j.1574-6968.1998.tb13221.x

Cite

Citations (140)

Construction of a severely attenuated mutant of Mycobacterium tuberculosis for reducing risk to laboratory workers

Tuberculosis (2008)

Farahnaz Movahedzadeh Ann Williams Simon Clark Graham Hatch Debbie A. Smith

Strain (injury)

Mycobacterium tuberculosis complex

10.1016/j.tube.2008.02.008

Cite

Citations (2)

Identification of Morpholino Thiophenes as Novel Mycobacterium tuberculosis Inhibitors, Targeting QcrB

Journal of Medicinal Chemistry (2018)

Laura A. T. Cleghorn Peter C. Ray Joshua Odingo Anuradha Kumar Heather Wescott

With the emergence of multidrug-resistant strains of Mycobacterium tuberculosis there is a pressing need for new oral drugs with novel mechanisms of action. Herein, we describe the identification of a novel morpholino-thiophenes (MOT) series following phenotypic screening of the Eli Lilly corporate library against M. tuberculosis strain H37Rv. The design, synthesis, and structure-activity relationships of a range of analogues around the confirmed actives are described. Optimized leads with potent whole cell activity against H37Rv, no cytotoxicity flags, and in vivo efficacy in an acute murine model of infection are described. Mode-of-action studies suggest that the novel scaffold targets QcrB, a subunit of the menaquinol cytochrome c oxidoreductase, part of the bc1-aa3-type cytochrome c oxidase complex that is responsible for driving oxygen-dependent respiration.

Morpholino

Mode of Action

Structure–activity relationship

Phenotypic screening

10.1021/acs.jmedchem.8b00172

Cite

Citations (49)

Methionine Sulfoximine Resistance in Mycobacterium tuberculosis Is Due to a Single Nucleotide Deletion Resulting in Increased Expression of the Major Glutamine Synthetase, GlnA1

Microbial Drug Resistance (2011)

Paul Carroll Simon J. Waddell Philip D. Butcher Tanya Parish

We investigated the effect of methionine sulfoximine (MetSox), a potent inhibitor of glutamine synthetase, on Mycobacterium tuberculosis. M. tuberculosis encodes four glutamine synthetases, of which MetSox targets the type I enzyme encoded by glnA1. Trancriptional profiling revealed that glutamate synthetase (gltB) and a type II glutamine synthetase (glnA3) were induced after exposure to MetSox. In addition, we observed a high rate (10−5) of spontaneous resistance to MetSox. All resistant strains had a single-nucleotide deletion in the 5' region of glnA1, and Western analysis revealed that GlnA1 expression was increased in resistant as compared with sensitive strains. These data show that M. tuberculosis can respond to the effect of MetSox inhibition either by up-regulation of GlnA3 or by GlnA1. The high frequency of resistance suggests that MetSox and other compounds specifically targeting GlnA1 are not likely to become successful anti-mycobacterial agents.

10.1089/mdr.2010.0125

Cite

Citations (11)

A Novel Antimycobacterial Compound Acts as an Intracellular Iron Chelator

Antimicrobial Agents and Chemotherapy (2015)

Marte S. Dragset Giovanna Poce Salvatore Alfonso Teresita Padilla‐Benavides Thomas R. Ioerger

ABSTRACT Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis . Mycobacterial iron uptake and metabolism are therefore attractive targets for antitubercular drug development. Resistance mutations against a novel pyrazolopyrimidinone compound (PZP) that is active against M. tuberculosis have been identified within the gene cluster encoding the ESX-3 type VII secretion system. ESX-3 is required for mycobacterial iron acquisition through the mycobactin siderophore pathway, which could indicate that PZP restricts mycobacterial growth by targeting ESX-3 and thus iron uptake. Surprisingly, we show that ESX-3 is not the cellular target of the compound. We demonstrate that PZP indeed targets iron metabolism; however, we found that instead of inhibiting uptake of iron, PZP acts as an iron chelator, and we present evidence that the compound restricts mycobacterial growth by chelating intrabacterial iron. Thus, we have unraveled the unexpected mechanism of a novel antimycobacterial compound.

Antimycobacterial

10.1128/aac.05114-14

Cite

Citations (34)

Design and Synthesis of Pyridyl and 2-Hydroxyphenyl Chalcones with Antitubercular Activity.

Kelphina Aziafor Ketan Rupareila Mire Zloh Tanya Parish Federico Brucoli

A focussed library of pyridyl and 2-hydroxyphenyl chalcones were synthesized and tested for growth inhibitory activity against Mycobacterium tuberculosis H37Rv, and normal and cancer breast cell lines. Pyridyl chalcones bearing lipophilic A-ring, e.g., dichloro-phenyl- (14), pyrene-1-yl (20)- and biphenyl-4-yl (21) moieties, were found to be the most potent of the series inhibiting the growth of M. tuberculosis H37Rv with IC90 values ranging from 8.9 – 28 µM. Aryl chalcones containing a 3-methoxyphenyl A-ring and either p-Br-phenyl (25) or p-Cl- phenyl (26) B-rings showed an IC90 value of 28 μM. Aryl-chalcones were generally less toxic to HepG2 cells compared to pyridyl-chalcones. Dose-dependent antiproliferative activity against MDA468 cells was observed for trimethoxy-phenyl (16) and anthracene-9-yl (19) pyridyl-chalcones with IC50 values of 0.7 and 0.3 µM, respectively. Docking studies revealed that chalone 20 was predicted to bind to the M. tuberculosis protein tyrosine phosphatases B (PtpB) with higher affinity compared to a previously reported PtpB inhibitor.

Chalcone

IC50

Quinoxaline

Mycobacterium smegmatis

10.20944/preprints202407.0139.v1

Cite

Citations (2)

Electroporation of Mycobacteria

Humana Press eBooks (2003)

Tanya Parish Neil G. Stoker

The study of mycobacterial genomes has exploded during the last 10 yr. Initially, no systems were available for the du-ect manipulation of mycobacterial genes in mycobactena, so Escherichia coli was used as the primary cloning host. Several genomic libraries were created (1–5) in E. coli. Although these proved useful for the ldentification of many protein antigens (6), the use of E coli as a cloning host has several limitations. It is now known that many mycobacterial promoters do not function at all in E. coli; therefore, it is difficult to study the expression and control of mycobacterial genes in such a host. In addition, certain posttranslational modifications of proteins do not take place in E. coli and therefore the antigenicity and properties of proteins expressed in E coli may differ (7–9).

Cloning (programming)

Antigenicity

10.1385/0-89603-471-2:129

Cite

Citations (41)