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  1. Article ; Online: Mycobacterial membrane protein Large 3-like-family proteins in bacteria, protozoa, fungi, plants, and animals: A bioinformatics and structural investigation.

    Malwal, Satish R / Oldfield, Eric

    Proteins

    2021  Volume 90, Issue 3, Page(s) 776–790

    Abstract: Lipid transporters play an important role in most if not all organisms, ranging from bacteria to humans. For example, in Mycobacterium tuberculosis, the trehalose monomycolate transporter MmpL3 is involved in cell wall biosynthesis, while in humans, ... ...

    Abstract Lipid transporters play an important role in most if not all organisms, ranging from bacteria to humans. For example, in Mycobacterium tuberculosis, the trehalose monomycolate transporter MmpL3 is involved in cell wall biosynthesis, while in humans, cholesterol transporters are involved in normal cell function as well as in disease. Here, using structural and bioinformatics information, we propose that there are proteins that also contain "MmpL3-like" (MMPL) transmembrane (TM) domains in many protozoa, including Trypanosoma cruzi, as well as in the bacterium Staphylococcus aureus, where the fatty acid transporter FarE has the same set of "active-site" residues as those found in the mycobacterial MmpL3s, and in T. cruzi. We also show that there are strong sequence and predicted structural similarities between the TM proton-translocation domain seen in the X-ray structures of mycobacterial MmpL3s and several human as well as fungal lipid transporters, leading to the proposal that there are similar proteins in apicomplexan parasites, and in plants. The animal, fungal, apicomplexan, and plant proteins have larger extra-membrane domains than are found in the bacterial MmpL3, but they have a similar TM domain architecture, with the introduction of a (catalytically essential) Phe > His residue change, and a Ser/Thr H-bond network, involved in H
    MeSH term(s) Amino Acid Sequence ; Bacterial Proteins/chemistry ; Biological Transport ; Catalytic Domain ; Cholesterol/chemistry ; Cord Factors/chemistry ; Fungi ; Membrane Transport Proteins/chemistry ; Models, Molecular ; Mycobacterium tuberculosis/metabolism ; Protein Binding ; Protein Conformation ; Protein Domains ; Staphylococcus aureus ; Structure-Activity Relationship ; Trypanosoma cruzi
    Chemical Substances Bacterial Proteins ; Cord Factors ; Membrane Transport Proteins ; trehalose monomycolate ; Cholesterol (97C5T2UQ7J)
    Language English
    Publishing date 2021-11-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 806683-8
    ISSN 1097-0134 ; 0887-3585
    ISSN (online) 1097-0134
    ISSN 0887-3585
    DOI 10.1002/prot.26273
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Editor's Note: Relates to: 'Immuno-antibiotics: targeting microbial metabolic pathways sensed by unconventional T cells'.

    Eberl, Matthias / Oldfield, Eric / Herrmann, Thomas

    Immunotherapy advances

    2021  Volume 1, Issue 1, Page(s) ltab023

    Language English
    Publishing date 2021-11-19
    Publishing country England
    Document type Editorial
    ISSN 2732-4303
    ISSN (online) 2732-4303
    DOI 10.1093/immadv/ltab023
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Tuberculosis terpene targets.

    Oldfield, Eric

    Chemistry & biology

    2015  Volume 22, Issue 4, Page(s) 437–438

    Abstract: In this issue, Young, Moody, and colleagues report the discovery of an isomer of the Mycobacterium tuberculosis (Mtb) virulence factor 1-tuberculosinyl adenosine, N(6)-tuberculosinyl adenosine, in mice infected with tuberculosis. These Mtb-derived ... ...

    Abstract In this issue, Young, Moody, and colleagues report the discovery of an isomer of the Mycobacterium tuberculosis (Mtb) virulence factor 1-tuberculosinyl adenosine, N(6)-tuberculosinyl adenosine, in mice infected with tuberculosis. These Mtb-derived terpene compounds may serve as sensitive and specific biomarkers of infection.
    MeSH term(s) Animals ; Lipids/biosynthesis ; Mycobacterium tuberculosis/metabolism ; Nucleosides/analysis ; Terpenes/chemistry ; Tuberculosis/diagnosis
    Chemical Substances Lipids ; Nucleosides ; Terpenes
    Language English
    Publishing date 2015-04-23
    Publishing country United States
    Document type Comment ; Journal Article
    ZDB-ID 917827-2
    ISSN 1879-1301 ; 1074-5521
    ISSN (online) 1879-1301
    ISSN 1074-5521
    DOI 10.1016/j.chembiol.2015.04.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: COVID-19 and Other Pandemics: How Might They Be Prevented?

    Oldfield, Eric / Malwal, Satish R

    ACS infectious diseases

    2020  Volume 6, Issue 7, Page(s) 1563–1566

    Abstract: Pandemics such as influenza, smallpox, and plague have caused the loss of hundreds of millions of lives and have occurred for many centuries. Fortunately, they have been largely eliminated by the use of vaccinations and drugs. More recently, Severe Acute ...

    Abstract Pandemics such as influenza, smallpox, and plague have caused the loss of hundreds of millions of lives and have occurred for many centuries. Fortunately, they have been largely eliminated by the use of vaccinations and drugs. More recently, Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and now Coronavirus Disease 2019 (COVID-19) have arisen, and given the current absence of highly effective approved vaccines or drugs, brute-force approaches involving physical barriers are being used to counter virus spread. A major basis for physical protection from respiratory infections is eye, nose, and mouth protection. However, eye protection with goggles is problematic due to "fogging", while nose/mouth protection is complicated by the breathing difficulties associated with non-valved respirators. Here, we give a brief review of the origins and development of face masks and eye protection to counter respiratory infections on the basis of experiments conducted 100 years ago, work that was presaged by the first use of personal protective equipment, "PPE", by the plague doctors of the 17
    MeSH term(s) Betacoronavirus ; COVID-19 ; Coronavirus Infections/prevention & control ; Coronavirus Infections/transmission ; Coronavirus Infections/virology ; Eye Protective Devices/history ; History, 17th Century ; History, 20th Century ; History, 21st Century ; Humans ; Infection Control/history ; Infection Control/instrumentation ; Infection Control/methods ; Influenza Pandemic, 1918-1919/history ; Masks/history ; Pandemics/prevention & control ; Pneumonia, Viral/prevention & control ; Pneumonia, Viral/transmission ; Pneumonia, Viral/virology ; SARS-CoV-2 ; Severe Acute Respiratory Syndrome/history ; Severe Acute Respiratory Syndrome/prevention & control ; Severe Acute Respiratory Syndrome/transmission ; Severe Acute Respiratory Syndrome/virology
    Keywords covid19
    Language English
    Publishing date 2020-06-01
    Publishing country United States
    Document type Historical Article ; Journal Article ; Review
    ISSN 2373-8227
    ISSN (online) 2373-8227
    DOI 10.1021/acsinfecdis.0c00291
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Immuno-antibiotics: targeting microbial metabolic pathways sensed by unconventional T cells.

    Eberl, Matthias / Oldfield, Eric / Herrmann, Thomas

    Immunotherapy advances

    2021  Volume 1, Issue 1, Page(s) ltab005

    Abstract: Human Vγ9/Vδ2 T cells, mucosal-associated invariant T (MAIT) cells, and other unconventional T cells are specialised in detecting microbial metabolic pathway intermediates that are absent in humans. The recognition by such semi-invariant innate-like T ... ...

    Abstract Human Vγ9/Vδ2 T cells, mucosal-associated invariant T (MAIT) cells, and other unconventional T cells are specialised in detecting microbial metabolic pathway intermediates that are absent in humans. The recognition by such semi-invariant innate-like T cells of compounds like (
    Language English
    Publishing date 2021-04-05
    Publishing country England
    Document type Journal Article ; Review
    ISSN 2732-4303
    ISSN (online) 2732-4303
    DOI 10.1093/immadv/ltab005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: COVID-19 and Other Pandemics

    Oldfield, Eric / Malwal, Satish R.

    ACS Infectious Diseases

    How Might They Be Prevented?

    2020  Volume 6, Issue 7, Page(s) 1563–1566

    Keywords covid19
    Language English
    Publisher American Chemical Society (ACS)
    Publishing country us
    Document type Article ; Online
    ISSN 2373-8227
    DOI 10.1021/acsinfecdis.0c00291
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article: COVID-19 and Other Pandemics: How Might They Be Prevented?

    Oldfield, Eric / Malwal, Satish R

    ACS Infect Dis

    Abstract: Pandemics such as influenza, smallpox, and plague have caused the loss of hundreds of millions of lives and have occurred for many centuries. Fortunately, they have been largely eliminated by the use of vaccinations and drugs. More recently, Severe Acute ...

    Abstract Pandemics such as influenza, smallpox, and plague have caused the loss of hundreds of millions of lives and have occurred for many centuries. Fortunately, they have been largely eliminated by the use of vaccinations and drugs. More recently, Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and now Coronavirus Disease 2019 (COVID-19) have arisen, and given the current absence of highly effective approved vaccines or drugs, brute-force approaches involving physical barriers are being used to counter virus spread. A major basis for physical protection from respiratory infections is eye, nose, and mouth protection. However, eye protection with goggles is problematic due to "fogging", while nose/mouth protection is complicated by the breathing difficulties associated with non-valved respirators. Here, we give a brief review of the origins and development of face masks and eye protection to counter respiratory infections on the basis of experiments conducted 100 years ago, work that was presaged by the first use of personal protective equipment, "PPE", by the plague doctors of the 17th Century. The results of the review lead to two conclusions: first, that eye protection using filtered eye masks be used to prevent ocular transmission; second, that new, pre-filtered, valved respirators be used to even more effectively block viral transmission.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #456955
    Database COVID19

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  8. Article ; Online: A Structural and Bioinformatics Investigation of a Fungal Squalene Synthase and Comparisons with Other Membrane Proteins.

    Malwal, Satish R / Shang, Na / Liu, Weidong / Li, Xian / Zhang, Lilan / Chen, Chun-Chi / Guo, Rey-Ting / Oldfield, Eric

    ACS omega

    2022  Volume 7, Issue 26, Page(s) 22601–22612

    Abstract: There is interest in the development of drugs to treat fungal infections due to the increasing threat of drug resistance, and here, we report the first crystallographic structure of the catalytic domain of a fungal squalene synthase (SQS), ...

    Abstract There is interest in the development of drugs to treat fungal infections due to the increasing threat of drug resistance, and here, we report the first crystallographic structure of the catalytic domain of a fungal squalene synthase (SQS),
    Language English
    Publishing date 2022-06-17
    Publishing country United States
    Document type Journal Article
    ISSN 2470-1343
    ISSN (online) 2470-1343
    DOI 10.1021/acsomega.2c01924
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: In Vivo Efficacy of SQ109 against

    Baek, Kyung-Hwa / Phan, Trong-Nhat / Malwal, Satish R / Lee, Hyeryon / Li, Zhu-Hong / Moreno, Silvia N J / Oldfield, Eric / No, Joo Hwan

    Biomedicines

    2022  Volume 10, Issue 3

    Abstract: SQ109 is an anti-tubercular drug candidate that has completed Phase IIb/III clinical trials for tuberculosis and has also been shown to exhibit potent in vitro efficacy against protozoan parasites ... ...

    Abstract SQ109 is an anti-tubercular drug candidate that has completed Phase IIb/III clinical trials for tuberculosis and has also been shown to exhibit potent in vitro efficacy against protozoan parasites including
    Language English
    Publishing date 2022-03-14
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2720867-9
    ISSN 2227-9059
    ISSN 2227-9059
    DOI 10.3390/biomedicines10030670
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Targeting isoprenoid biosynthesis for drug discovery: bench to bedside.

    Oldfield, Eric

    Accounts of chemical research

    2010  Volume 43, Issue 9, Page(s) 1216–1226

    Abstract: The isoprenoid biosynthesis pathways produce the largest class of small molecules in Nature: isoprenoids (also called terpenoids). Not surprisingly then, isoprenoid biosynthesis is a target for drug discovery, and many drugs--such as Lipitor (used to ... ...

    Abstract The isoprenoid biosynthesis pathways produce the largest class of small molecules in Nature: isoprenoids (also called terpenoids). Not surprisingly then, isoprenoid biosynthesis is a target for drug discovery, and many drugs--such as Lipitor (used to lower cholesterol), Fosamax (used to treat osteoporosis), and many anti-infectives--target isoprenoid biosynthesis. However, drug resistance in malaria, tuberculosis, and staph infections is rising, cheap and effective drugs for the neglected tropical diseases are lacking, and progress in the development of anticancer drugs is relatively slow. Isoprenoid biosynthesis is thus an attractive target, and in this Account, I describe developments in four areas, using in each case knowledge derived from one area of chemistry to guide the development of inhibitors (or drug leads) in another, seemingly unrelated, area. First, I describe mechanistic studies of the enzyme IspH, which is present in malaria parasites and most pathogenic bacteria, but not in humans. IspH is a 4Fe-4S protein and produces the five-carbon (C5) isoprenoids IPP (isopentenyl diphosphate) and DMAPP (dimethylallyl diphosphate) from HMBPP (E-1-hydroxy-2-methyl-but-2-enyl-4-diphosphate) via a 2H(+)/2e(-) reduction (of an allyl alcohol to an alkene). The mechanism is unusual in that it involves organometallic species: "metallacycles" (η(2)-alkenes) and η(1)/η(3)-allyls. These observations lead to novel alkyne inhibitors, which also form metallacycles. Second, I describe structure-function-inhibition studies of FPP synthase, the macromolecule that condenses IPP and DMAPP to the sesquiterpene farnesyl diphosphate (FPP) in a "head-to-tail" manner. This enzyme uses a carbocation mechanism and is potently inhibited by bone resorption drugs (bisphosphonates), which I show are also antiparasitic agents that block sterol biosynthesis in protozoa. Moreover, "lipophilic" bisphosphonates inhibit protein prenylation and invasiveness in tumor cells, in addition to activating γδ T-cells to kill tumor cells, and are important new leads in oncology. Third, I describe structural and inhibition studies of a "head-to-head" triterpene synthase, dehydrosqualene synthase (CrtM), from Staphylococcus aureus. CrtM catalyzes the first committed step in biosynthesis of the carotenoid virulence factor staphyloxanthin: the condensation of two FPP molecules to produce a cyclopropane (presqualene diphosphate). The structure of CrtM is similar to that of human squalene synthase (SQS), and some SQS inhibitors (originally developed as cholesterol-lowering drugs) block staphyloxanthin biosynthesis. Treated bacteria are white and nonvirulent (because they lack the carotenoid shield that protects them from reactive oxygen species produced by neutrophils), rendering them susceptible to innate immune system clearance--a new therapeutic approach. And finally, I show that the heart drug amiodarone, also known to have antifungal activity, blocks ergosterol biosynthesis at the level of oxidosqualene cyclase in Trypanosoma cruzi, work that has led to its use in the clinic as a novel antiparasitic agent. In each of these four examples, I use information from one area (organometallic chemistry, bone resorption drugs, cholesterol-lowering agents, heart disease) to develop drug leads in an unrelated area: a "knowledge-based" approach that represents an important advance in the search for new drugs.
    MeSH term(s) Animals ; Anti-Infective Agents/chemistry ; Anti-Infective Agents/metabolism ; Anti-Infective Agents/therapeutic use ; Bacterial Proteins/chemistry ; Bacterial Proteins/metabolism ; Diphosphonates/chemistry ; Diphosphonates/therapeutic use ; Drug Evaluation, Preclinical ; Farnesyl-Diphosphate Farnesyltransferase/chemistry ; Farnesyl-Diphosphate Farnesyltransferase/metabolism ; Humans ; Leishmaniasis/drug therapy ; Mice ; Pamidronate ; Staphylococcal Infections/drug therapy ; Staphylococcus aureus/enzymology ; Terpenes/chemistry ; Terpenes/metabolism ; Terpenes/therapeutic use ; Xanthophylls/biosynthesis ; Xanthophylls/chemistry ; Xanthophylls/therapeutic use
    Chemical Substances Anti-Infective Agents ; Bacterial Proteins ; Diphosphonates ; Terpenes ; Xanthophylls ; staphyloxanthin (71869-01-7) ; CrtM protein, Staphylococcus aureus (EC 1.3.-) ; Farnesyl-Diphosphate Farnesyltransferase (EC 2.5.1.21) ; Pamidronate (OYY3447OMC)
    Language English
    Publishing date 2010-06-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1483291-4
    ISSN 1520-4898 ; 0001-4842
    ISSN (online) 1520-4898
    ISSN 0001-4842
    DOI 10.1021/ar100026v
    Database MEDical Literature Analysis and Retrieval System OnLINE

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