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Good, James A. D.
Alternative names
Publications (9 of 9) Show all publications
Flentie, K., Harrison, G. A., Tükenmez, H., Livny, J., Good, J. A. D., Sarkar, S., . . . Stallings, C. L. (2019). Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America, 116(21), 10510-10517
Open this publication in new window or tab >>Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis
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2019 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 21, p. 10510-10517Article in journal (Refereed) Published
Abstract [en]

Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.

Place, publisher, year, edition, pages
The National Academy of Scionces of the United States of America, 2019
Keywords
Mycobacterium tuberculosis, drug tolerance, antibiotic resistance, isoniazid, respiration
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-159857 (URN)10.1073/pnas.1818009116 (DOI)000468403400054 ()31061116 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Foundation for Strategic Research The Kempe FoundationsNIH (National Institute of Health)
Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-06-10Bibliographically approved
Good, J. A. D., Kulén, M., Silver, J., Krishnan, K. S., Bahnan, W., Núñez-Otero, C., . . . Almqvist, F. (2017). Thiazolino 2-pyridone amide isosteres as inhibitors of Chlamydia trachomatis infectivity. Journal of Medicinal Chemistry, 60(22), 9393-9399
Open this publication in new window or tab >>Thiazolino 2-pyridone amide isosteres as inhibitors of Chlamydia trachomatis infectivity
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2017 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 60, no 22, p. 9393-9399Article in journal (Refereed) Published
Abstract [en]

Chlamydia trachomatis is a global health burden due to its prevalence as a sexually transmitted disease and as the causative agent of the eye infection trachoma. We recently discovered 3-amido thiazolino 2-pyridones which attenuated C. trachomatis infectivity without affecting host cell or commensal bacteria viability. We present here the synthesis and evaluation of nonhydrolyzable amide isosteres based on this class, leading to highly potent 1,2,3-triazole based infectivity inhibitors (EC50 ≤ 20 nM).

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-142974 (URN)10.1021/acs.jmedchem.7b00716 (DOI)000416500200019 ()29053275 (PubMedID)
Available from: 2017-12-14 Created: 2017-12-14 Last updated: 2018-08-28Bibliographically approved
Good, J. A. D., Andersson, C., Hansen, S., Wall, J., Krishnan, S., Begum, A., . . . Johansson, J. (2016). Attenuating Listeria monocytogenes virulence by targeting the regulatory protein PrfA. Cell chemical biology, 23(3), 404-414
Open this publication in new window or tab >>Attenuating Listeria monocytogenes virulence by targeting the regulatory protein PrfA
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2016 (English)In: Cell chemical biology, ISSN 2451-9448, Vol. 23, no 3, p. 404-414Article in journal (Refereed) Published
Abstract [en]

The transcriptional activator PrfA, a member of the Crp/Fnr family, controls the expression of some key virulence factors necessary for infection by the human bacterial pathogen Listeria monocytogenes. Phenotypic screening identified ring-fused 2-pyridone molecules that at low micromolar concentrations attenuate L. monocytogenes infectivity by reducing the expression of virulence genes, without compromising bacterial growth. These inhibitors bind the transcriptional regulator PrfA and decrease its affinity for the consensus DNA binding site. Structural characterization of this interaction revealed that one of the ring-fused 2-pyridones, compound 1, binds within a hydrophobic pocket, located between the C- and N-terminal domains of PrfA, and interacts with residues important for PrfA activation. This indicates that these inhibitors maintain the DNA-binding helix-turn-helix motif of PrfA in a disordered state, thereby preventing a PrfA:DNA interaction. Ring-fused 2-pyridones represent a new class of chemical probes for studying virulence in L. monocytogenes.

National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-114083 (URN)10.1016/j.chembiol.2016.02.013 (DOI)000381508300013 ()26991105 (PubMedID)
Note

Originally published in manuscipt form in thesis.

Available from: 2016-01-12 Created: 2016-01-12 Last updated: 2018-06-07Bibliographically approved
Varga, M. G., Shaffer, C. L., Sierra, J. C., Suarez, G., Piazuelo, M. B., Whitaker, M. E., . . . Peek, R. M. (2016). Pathogenic Helicobacter pylori strains translocate DNA and activate TLR9 via the cancer-associated cag type IV secretion system. Oncogene, 35(48), 6262-6269
Open this publication in new window or tab >>Pathogenic Helicobacter pylori strains translocate DNA and activate TLR9 via the cancer-associated cag type IV secretion system
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2016 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 35, no 48, p. 6262-6269Article in journal (Refereed) Published
Abstract [en]

Helicobacter pylori (H. pylori) is the strongest identified risk factor for gastric cancer, the third most common cause of cancer-related death worldwide. An H. pylori constituent that augments cancer risk is the strain-specific cag pathogenicity island, which encodes a type IV secretion system (T4SS) that translocates a pro-inflammatory and oncogenic protein, CagA, into epithelial cells. However, the majority of persons colonized with CagA+ H. pylori strains do not develop cancer, suggesting that other microbial effectors also have a role in carcinogenesis. Toll-like receptor 9 (TLR9) is an endosome bound, innate immune receptor that detects and responds to hypo-methylated CpG DNA motifs that are most commonly found in microbial genomes. High-expression tlr9 polymorphisms have been linked to the development of premalignant lesions in the stomach. We now demonstrate that levels of H. pylori-mediated TLR9 activation and expression are directly related to gastric cancer risk in human populations. Mechanistically, we show for the first time that the H. pylori cancer-associated cag T4SS is required for TLR9 activation and that H. pylori DNA is actively translocated by the cag T4SS to engage this host receptor. Activation of TLR9 occurs through a contact-dependent mechanism between pathogen and host, and involves transfer of microbial DNA that is both protected as well as exposed during transport. These results indicate that TLR9 activation via the cag island may modify the risk for malignancy within the context of H. pylori infection and provide an important framework for future studies investigating the microbial-epithelial interface in gastric carcinogenesis.

Place, publisher, year, edition, pages
Nature Publishing Group, 2016
National Category
Chemical Sciences Microbiology in the medical area Cancer and Oncology Medical Genetics
Identifiers
urn:nbn:se:umu:diva-128864 (URN)10.1038/onc.2016.158 (DOI)000388857700010 ()
Note

Supplementary information available for this article at http://www.nature.com/onc/journal/v35/n48/suppinfo/onc2016158s1.html

Available from: 2016-12-16 Created: 2016-12-16 Last updated: 2018-06-09Bibliographically approved
Shaffer, C. L., Good, J. A. D., Kumar, S., Krishnan, K. S., Gaddy, J. A., Loh, J. T., . . . Hadjifrangiskou, M. (2016). Peptidomimetic Small Molecules Disrupt Type IV Secretion System Activity in Diverse Bacterial Pathogens. mBio, 7(2), Article ID e00221-16.
Open this publication in new window or tab >>Peptidomimetic Small Molecules Disrupt Type IV Secretion System Activity in Diverse Bacterial Pathogens
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2016 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 7, no 2, article id e00221-16Article in journal (Refereed) Published
Abstract [en]

Bacteria utilize complex type IV secretion systems (T4SSs) to translocate diverse effector proteins or DNA into target cells. Despite the importance of T4SSs in bacterial pathogenesis, the mechanism by which these translocation machineries deliver cargo across the bacterial envelope remains poorly understood, and very few studies have investigated the use of synthetic molecules to disrupt T4SS-mediated transport. Here, we describe two synthetic small molecules (C10 and KSK85) that disrupt T4SS-dependent processes in multiple bacterial pathogens. Helicobacter pylori exploits a pilus appendage associated with the cag T4SS to inject an oncogenic effector protein (CagA) and peptidoglycan into gastric epithelial cells. In H. pylori, KSK85 impedes biogenesis of the pilus appendage associated with the cag T4SS, while C10 disrupts cag T4SS activity without perturbing pilus assembly. In addition to the effects in H. pylori, we demonstrate that these compounds disrupt interbacterial DNA transfer by conjugative T4SSs in Escherichia coli and impede vir T4SS-mediated DNA delivery by Agrobacterium tumefaciens in a plant model of infection. Of note, C10 effectively disarmed dissemination of a derepressed IncF plasmid into a recipient bacterial population, thus demonstrating the potential of these compounds in mitigating the spread of antibiotic resistance determinants driven by conjugation. To our knowledge, this study is the first report of synthetic small molecules that impair delivery of both effector protein and DNA cargos by diverse T4SSs. IMPORTANCE Many human and plant pathogens utilize complex nanomachines called type IV secretion systems (T4SSs) to transport proteins and DNA to target cells. In addition to delivery of harmful effector proteins into target cells, T4SSs can disseminate genetic determinants that confer antibiotic resistance among bacterial populations. In this study, we sought to identify compounds that disrupt T4SS-mediated processes. Using the human gastric pathogen H. pylori as a model system, we identified and characterized two small molecules that prevent transfer of an oncogenic effector protein to host cells. We discovered that these small molecules also prevented the spread of antibiotic resistance plasmids in E. coli populations and diminished the transfer of tumor-inducing DNA from the plant pathogen A. tumefaciens to target cells. Thus, these compounds are versatile molecular tools that can be used to study and disarm these important bacterial machines.

National Category
Microbiology
Identifiers
urn:nbn:se:umu:diva-124000 (URN)10.1128/mBio.00221-16 (DOI)000377768700071 ()
Funder
Swedish Research Council Formas, 621-2010-4730Knut and Alice Wallenberg Foundation
Available from: 2016-07-13 Created: 2016-07-07 Last updated: 2018-06-07Bibliographically approved
Good, J. A. D., Silver, J., Nunez-Otero, C., Bahnan, W., Krishnan, K. S., Salin, O., . . . Almqvist, F. (2016). Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity. Journal of Medicinal Chemistry, 59(5), 2094-2108
Open this publication in new window or tab >>Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity
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2016 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 5, p. 2094-2108Article in journal (Refereed) Published
Abstract [en]

The bacterial pathogen Chlamydia trachomatis is a global health burden currently treated with broad-spectrum antibiotics which disrupt commensal bacteria. We recently identified a compound through phenotypic screening that blocked infectivity of this intracellular pathogen without host cell toxicity (compound 1, KSK 120). Herein, we present the optimization of 1 to a class of thiazolino 2-pyridone amides that are highly efficacious (EC50 <= 100 nM) in attenuating infectivity across multiple serovars of C. trachomatis without host cell toxicity. The lead compound 21a exhibits reduced lipophilicity versus 1 and did not affect the growth or viability of representative commensal flora at 50 mu M. In microscopy studies, a highly active fluorescent analogue 37 localized inside the parasitiphorous inclusion, indicative of a specific targeting of bacterial components. In summary, we present a class of small molecules to enable the development of specific treatments for C. trachomatis.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016
National Category
Microbiology in the medical area Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-119066 (URN)10.1021/acs.jmedchem.5b01759 (DOI)000372043400031 ()26849778 (PubMedID)
Available from: 2016-04-20 Created: 2016-04-11 Last updated: 2018-06-07Bibliographically approved
Floyd, K. A., Moore, J. L., Eberly, A. R., Good, J. A. D., Shaffer, C. L., Zaver, H., . . . Hadjifrangiskou, M. (2015). Adhesive Fiber Stratification in Uropathogenic Escherichia coli Biofilms Unveils Oxygen-Mediated Control of Type 1 Pili. PLoS Pathogens, 11(3), Article ID e1004697.
Open this publication in new window or tab >>Adhesive Fiber Stratification in Uropathogenic Escherichia coli Biofilms Unveils Oxygen-Mediated Control of Type 1 Pili
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2015 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 11, no 3, article id e1004697Article in journal (Refereed) Published
Abstract [en]

Bacterial biofilms account for a significant number of hospital-acquired infections and complicate treatment options, because bacteria within biofilms are generally more tolerant to antibiotic treatment. This resilience is attributed to transient bacterial subpopulations that arise in response to variations in the microenvironment surrounding the biofilm. Here, we probed the spatial proteome of surface-associated single-species biofilms formed by uropathogenic Escherichia coli (UPEC), the major causative agent of community-acquired and catheter-associated urinary tract infections. We used matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) imaging mass spectrometry (IMS) to analyze the spatial proteome of intact biofilms in situ. MALDI-TOF IMS revealed protein species exhibiting distinct localizations within surface-associated UPEC biofilms, including two adhesive fibers critical for UPEC biofilm formation and virulence: type 1 pili (Fim) localized exclusively to the air-exposed region, while curli amyloid fibers localized to the air-liquid interface. Comparison of cells grown aerobically, fermentatively, or utilizing an alternative terminal electron acceptor showed that the phase-variable fim promoter switched to the "FF" orientation under oxygen-deplete conditions, leading to marked reduction of type 1 pili on the bacterial cell surface. Conversely, S pili whose expression is inversely related to fim expression were upregulated under anoxic conditions. Tethering the fim promoter in the "ON" orientation in anaerobically grown cells only restored type 1 pili production in the presence of an alternative terminal electron acceptor beyond oxygen. Together these data support the presence of at least two regulatory mechanisms controlling fim expression in response to oxygen availability and may contribute to the stratification of extracellular matrix components within the biofilm. MALDI IMS facilitated the discovery of these mechanisms, and we have demonstrated that this technology can be used to interrogate subpopulations within bacterial biofilms.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-103564 (URN)10.1371/journal.ppat.1004697 (DOI)000352201900026 ()25738819 (PubMedID)
Available from: 2015-05-25 Created: 2015-05-21 Last updated: 2018-06-07Bibliographically approved
Good, J. A. D., Berretta, G., Anthony, N. G. & Mackay, S. P. (2015). The Discovery and Development of Eg5 Inhibitors for the Clinic. In: Frank Kozielski (Ed.), Kinesins and Cancer: (pp. 27-52). Springer
Open this publication in new window or tab >>The Discovery and Development of Eg5 Inhibitors for the Clinic
2015 (English)In: Kinesins and Cancer / [ed] Frank Kozielski, Springer, 2015, p. 27-52Chapter in book (Refereed)
Abstract [en]

The mitotic kinesin Eg5 (also known as kinesin spindle protein, KSP, Kif11, a member of the kinesin-5 family) represents an attractive oncology drug target in the ongoing development of anti-mitotic drugs that selectively block mitosis through disruption to the mitotic spindle. In this state-of-the-art review, we outline the progress that has been made in the development of Eg5 inhibitors for clinical use. We evaluate the preclinical development and attributes of key Eg5 inhibitors that have undergone clinical evaluation or extensive preclinical optimisation, and discuss the medicinal chemistry strategies utilised in their design to overcome the challenges encountered during lead optimisation. We critically analyse the progress that has been made towards delivering clinical benefits, and the wider implications this has in the utility of mitotic kinesin inhibitors as prospective oncology drugs.

Place, publisher, year, edition, pages
Springer, 2015
Keywords
Anti-mitotic, Drug discovery, Multiple myeloma, Kinesins, Eg5
National Category
Chemical Sciences Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-106758 (URN)10.1007/978-94-017-9732-0_2 (DOI)978-94-017-9731-3 (ISBN)978-94-017-9732-0 (ISBN)
Available from: 2015-08-07 Created: 2015-08-07 Last updated: 2018-06-07Bibliographically approved
Krishnan, K. S., Bengtsson, C., Good, J. A. D., Mirkhanov, S., Chorell, E., Johansson, L.-Å. B. -. & Almqvist, F. (2013). Synthesis of fluorescent ring-fused 2-pyridone peptidomimetics. Journal of Organic Chemistry, 78(23), 12207-12213
Open this publication in new window or tab >>Synthesis of fluorescent ring-fused 2-pyridone peptidomimetics
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2013 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 78, no 23, p. 12207-12213Article in journal (Refereed) Published
Abstract [en]

Thiazolino fused 2-pyridones peptidomimetics are of significant biological importance due to their ability to interfere with adhesive fiber formation in uropathogenic Escherichia coli and oligomerization of amyloid fibres. We have developed an efficient synthetic route to fluorescent BODIPY analogues, with structural diversification from a key intermediate enabling introduction of C-2 substituents and late incorporation of the BODIPY moiety. A mild lithium halide mediated hydrolysis enabled preparation of peptidomimetic fluorophores with useful photophysical properties for further chemical biology applications.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2013
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-82342 (URN)10.1021/jo401844y (DOI)000328231600062 ()24161000 (PubMedID)
Funder
Swedish Research Council, 621-2010-4730
Available from: 2013-10-30 Created: 2013-10-30 Last updated: 2018-06-08Bibliographically approved
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