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  1. Article ; Online: Pyrazinamide Susceptibility Is Driven by Activation of the SigE-Dependent Cell Envelope Stress Response in Mycobacterium tuberculosis.

    Thiede, Joshua M / Dillon, Nicholas A / Howe, Michael D / Aflakpui, Ranee / Modlin, Samuel J / Hoffner, Sven E / Valafar, Faramarz / Minato, Yusuke / Baughn, Anthony D

    mBio

    2022  Volume 13, Issue 1, Page(s) e0043921

    Abstract: Pyrazinamide (PZA) plays a crucial role in first-line tuberculosis drug therapy. Unlike other antimicrobial agents, PZA is active against Mycobacterium tuberculosis only at low pH. The basis for this conditional drug susceptibility remains undefined. In ... ...

    Abstract Pyrazinamide (PZA) plays a crucial role in first-line tuberculosis drug therapy. Unlike other antimicrobial agents, PZA is active against Mycobacterium tuberculosis only at low pH. The basis for this conditional drug susceptibility remains undefined. In this study, we utilized a genome-wide approach to interrogate potentiation of PZA action. We found that mutations in numerous genes involved in central metabolism as well as cell envelope maintenance and stress response are associated with PZA resistance. Further, we demonstrate that constitutive activation of the cell envelope stress response can drive PZA susceptibility independent of environmental pH. Consequently, exposure to peptidoglycan synthesis inhibitors, such as beta-lactams and d-cycloserine, potentiate PZA action through triggering this response. These findings illuminate a regulatory mechanism for conditional PZA susceptibility and reveal new avenues for enhancing potency of this important drug through targeting activation of the cell envelope stress response.
    MeSH term(s) Humans ; Pyrazinamide/therapeutic use ; Mycobacterium tuberculosis/genetics ; Amidohydrolases/metabolism ; Antitubercular Agents/pharmacology ; Tuberculosis/microbiology ; Mutation ; Microbial Sensitivity Tests
    Chemical Substances Pyrazinamide (2KNI5N06TI) ; Amidohydrolases (EC 3.5.-) ; Antitubercular Agents
    Language English
    Publishing date 2022-02-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2557172-2
    ISSN 2150-7511 ; 2161-2129
    ISSN (online) 2150-7511
    ISSN 2161-2129
    DOI 10.1128/mbio.00439-21
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Synthesis and biological evaluation of orally active prodrugs and analogs of para-aminosalicylic acid (PAS).

    Hegde, Pooja V / Howe, Michael D / Zimmerman, Matthew D / Boshoff, Helena I M / Sharma, Sachin / Remache, Brianna / Jia, Ziyi / Pan, Yan / Baughn, Anthony D / Dartois, Veronique / Aldrich, Courtney C

    European journal of medicinal chemistry

    2022  Volume 232, Page(s) 114201

    Abstract: Tuberculosis (TB) is one of the world's most deadly infectious diseases resulting in nearly 1.3 million deaths annually and infecting nearly one-quarter of the population. para-Aminosalicylic acid (PAS), an important second-line agent for treating drug- ... ...

    Abstract Tuberculosis (TB) is one of the world's most deadly infectious diseases resulting in nearly 1.3 million deaths annually and infecting nearly one-quarter of the population. para-Aminosalicylic acid (PAS), an important second-line agent for treating drug-resistant Mycobacterium tuberculosis, has moderate bioavailability and rapid clearance that necessitate high daily doses of up to 12 g per day, which in turn causes severe gastrointestinal disturbances presumably by disruption of gut microbiota and host epithelial cells. We first synthesized a series of alkyl, acyloxy and alkyloxycarbonyloxyalkyl ester prodrugs to increase the oral bioavailability and thereby prevent intestinal accumulation as well as undesirable bioactivation by the gut microbiome to non-natural folate species that exhibit cytotoxicity. The pivoxyl prodrug of PAS was superior to all of the prodrugs examined and showed nearly quantitative absorption. While the conceptually simple prodrug approach improved the oral bioavailability of PAS, it did not address the intrinsic rapid clearance of PAS mediated by N-acetyltransferase-1 (NAT-1). Thus, we next modified the PAS scaffold to reduce NAT-1 catalyzed inactivation by introduction of groups to sterically block N-acetylation and fluorination of the aryl ring of PAS to attenuate N-acetylation by electronically deactivating the para-amino group. Among the mono-fluorinated analogs prepared, 5-fluoro-PAS, exhibited the best activity and an 11-fold decreased rate of inactivation by NAT-1 that translated to a 5-fold improved exposure as measured by area-under-the-curve (AUC) following oral dosing to CD-1 mice. The pivoxyl prodrug and fluorination at the 5-position of PAS address the primary limitations of PAS and have the potential to revitalize this second-line TB drug.
    MeSH term(s) Aminosalicylic Acid/adverse effects ; Animals ; Antitubercular Agents/pharmacology ; Antitubercular Agents/therapeutic use ; Biological Availability ; Mice ; Prodrugs/pharmacology ; Prodrugs/therapeutic use ; Tuberculosis/drug therapy ; Tuberculosis, Multidrug-Resistant/drug therapy
    Chemical Substances Antitubercular Agents ; Prodrugs ; Aminosalicylic Acid (5B2658E0N2)
    Language English
    Publishing date 2022-02-19
    Publishing country France
    Document type Journal Article
    ZDB-ID 188597-2
    ISSN 1768-3254 ; 0009-4374 ; 0223-5234
    ISSN (online) 1768-3254
    ISSN 0009-4374 ; 0223-5234
    DOI 10.1016/j.ejmech.2022.114201
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Cephem-Pyrazinoic Acid Conjugates: Circumventing Resistance in Mycobacterium tuberculosis.

    Cole, Malcolm S / Howe, Michael D / Buonomo, Joseph A / Sharma, Sachin / Lamont, Elise A / Brody, Scott I / Mishra, Neeraj K / Minato, Yusuke / Thiede, Joshua M / Baughn, Anthony D / Aldrich, Courtney C

    Chemistry (Weinheim an der Bergstrasse, Germany)

    2022  Volume 28, Issue 51, Page(s) e202200995

    Abstract: Tuberculosis (TB) is a leading source of infectious disease mortality globally. Antibiotic-resistant strains comprise an estimated 10 % of new TB cases and present an urgent need for novel therapeutics. β-lactam antibiotics have traditionally been ... ...

    Abstract Tuberculosis (TB) is a leading source of infectious disease mortality globally. Antibiotic-resistant strains comprise an estimated 10 % of new TB cases and present an urgent need for novel therapeutics. β-lactam antibiotics have traditionally been ineffective against M. tuberculosis (Mtb), the causative agent of TB, due to the organism's inherent expression of β-lactamases that destroy the electrophilic β-lactam warhead. We have developed novel β-lactam conjugates, which exploit this inherent β-lactamase activity to achieve selective release of pyrazinoic acid (POA), the active form of a first-line TB drug. These conjugates are selectively active against M. tuberculosis and related mycobacteria, and activity is retained or even potentiated in multiple resistant strains and models. Preliminary mechanistic investigations suggest that both the POA "warhead" as well as the β-lactam "promoiety" contribute to the observed activity, demonstrating a codrug strategy with important implications for future TB therapy.
    MeSH term(s) Antitubercular Agents/pharmacology ; Antitubercular Agents/therapeutic use ; Humans ; Microbial Sensitivity Tests ; Mycobacterium tuberculosis ; Pyrazinamide/analogs & derivatives ; Pyrazinamide/pharmacology ; Tuberculosis/drug therapy ; Tuberculosis/microbiology ; beta-Lactams/pharmacology
    Chemical Substances Antitubercular Agents ; beta-Lactams ; Pyrazinamide (2KNI5N06TI) ; pyrazinoic acid (2WB23298SP)
    Language English
    Publishing date 2022-07-27
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 1478547-X
    ISSN 1521-3765 ; 0947-6539
    ISSN (online) 1521-3765
    ISSN 0947-6539
    DOI 10.1002/chem.202200995
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Methionine Antagonizes

    Howe, Michael D / Kordus, Shannon L / Cole, Malcolm S / Bauman, Allison A / Aldrich, Courtney C / Baughn, Anthony D / Minato, Yusuke

    Frontiers in cellular and infection microbiology

    2018  Volume 8, Page(s) 399

    Abstract: ... ...

    Abstract para
    MeSH term(s) 4-Aminobenzoic Acid/metabolism ; 4-Aminobenzoic Acid/pharmacology ; Aminosalicylic Acid/pharmacology ; Antitubercular Agents/pharmacology ; Bacterial Proteins/metabolism ; Biotin/metabolism ; Drug Antagonism ; Drug Resistance, Bacterial/genetics ; Folic Acid/pharmacology ; Methionine/metabolism ; Methionine/pharmacology ; Microbial Sensitivity Tests ; Mycobacterium/drug effects ; Mycobacterium/genetics ; Mycobacterium/growth & development ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/growth & development ; Mycobacterium tuberculosis/metabolism
    Chemical Substances Antitubercular Agents ; Bacterial Proteins ; Aminosalicylic Acid (5B2658E0N2) ; Biotin (6SO6U10H04) ; Folic Acid (935E97BOY8) ; Methionine (AE28F7PNPL) ; 4-Aminobenzoic Acid (TL2TJE8QTX)
    Language English
    Publishing date 2018-11-12
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2619676-1
    ISSN 2235-2988 ; 2235-2988
    ISSN (online) 2235-2988
    ISSN 2235-2988
    DOI 10.3389/fcimb.2018.00399
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Pathogen-specific antimicrobials engineered de novo through membrane-protein biomimicry.

    Simonson, Andrew W / Mongia, Agustey S / Aronson, Matthew R / Alumasa, John N / Chan, Dennis C / Lawanprasert, Atip / Howe, Michael D / Bolotsky, Adam / Mal, Tapas K / George, Christy / Ebrahimi, Aida / Baughn, Anthony D / Proctor, Elizabeth A / Keiler, Kenneth C / Medina, Scott H

    Nature biomedical engineering

    2021  Volume 5, Issue 5, Page(s) 467–480

    Abstract: Precision antimicrobials aim to kill pathogens without damaging commensal bacteria in the host, and thereby cure disease without antibiotic-associated dysbiosis. Here we report the de novo design of a synthetic host defence peptide that targets a ... ...

    Abstract Precision antimicrobials aim to kill pathogens without damaging commensal bacteria in the host, and thereby cure disease without antibiotic-associated dysbiosis. Here we report the de novo design of a synthetic host defence peptide that targets a specific pathogen by mimicking key molecular features of the pathogen's channel-forming membrane proteins. By exploiting physical and structural vulnerabilities within the pathogen's cellular envelope, we designed a peptide sequence that undergoes instructed tryptophan-zippered assembly within the mycolic acid-rich outer membrane of Mycobacterium tuberculosis to specifically kill the pathogen without collateral toxicity towards lung commensal bacteria or host tissue. These mycomembrane-templated assemblies elicit rapid mycobactericidal activity and enhance the potency of antibiotics by improving their otherwise poor diffusion across the rigid M. tuberculosis envelope with respect to agents that exploit transmembrane protein channels for antimycobacterial activity. This biomimetic strategy may aid the design of other narrow-spectrum antimicrobial peptides.
    MeSH term(s) Anti-Bacterial Agents/pharmacology ; Bacterial Outer Membrane/drug effects ; Bacterial Proteins/genetics ; Humans ; Lung/drug effects ; Lung/microbiology ; Membrane Proteins/genetics ; Molecular Mimicry ; Mycobacterium tuberculosis/drug effects ; Peptides/genetics ; Peptides/pharmacology
    Chemical Substances Anti-Bacterial Agents ; Bacterial Proteins ; Membrane Proteins ; Peptides
    Language English
    Publishing date 2021-01-04
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2157-846X
    ISSN (online) 2157-846X
    DOI 10.1038/s41551-020-00665-x
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  6. Article ; Online: Investigation of ( S)-(-)-Acidomycin: A Selective Antimycobacterial Natural Product That Inhibits Biotin Synthase.

    Bockman, Matthew R / Engelhart, Curtis A / Cramer, Julia D / Howe, Michael D / Mishra, Neeraj K / Zimmerman, Matthew / Larson, Peter / Alvarez-Cabrera, Nadine / Park, Sae Woong / Boshoff, Helena I M / Bean, James M / Young, Victor G / Ferguson, David M / Dartois, Veronique / Jarrett, Joseph T / Schnappinger, Dirk / Aldrich, Courtney C

    ACS infectious diseases

    2019  Volume 5, Issue 4, Page(s) 598–617

    Abstract: The synthesis, absolute stereochemical configuration, complete biological characterization, mechanism of action and resistance, and pharmacokinetic properties of ( S)-(-)-acidomycin are described. Acidomycin possesses promising antitubercular activity ... ...

    Abstract The synthesis, absolute stereochemical configuration, complete biological characterization, mechanism of action and resistance, and pharmacokinetic properties of ( S)-(-)-acidomycin are described. Acidomycin possesses promising antitubercular activity against a series of contemporary drug susceptible and drug-resistant M. tuberculosis strains (minimum inhibitory concentrations (MICs) = 0.096-6.2 μM) but is inactive against nontuberculosis mycobacteria and Gram-positive and Gram-negative pathogens (MICs > 1000 μM). Complementation studies with biotin biosynthetic pathway intermediates and subsequent biochemical studies confirmed acidomycin inhibits biotin synthesis with a K
    MeSH term(s) Animals ; Antitubercular Agents/chemical synthesis ; Antitubercular Agents/chemistry ; Antitubercular Agents/pharmacology ; Bacterial Proteins/antagonists & inhibitors ; Bacterial Proteins/chemistry ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Biological Products/chemical synthesis ; Biological Products/chemistry ; Biological Products/pharmacology ; Biotin/biosynthesis ; Caproates/chemical synthesis ; Caproates/chemistry ; Caproates/pharmacology ; Drug Resistance, Bacterial ; Humans ; Kinetics ; Mice ; Microbial Sensitivity Tests ; Mycobacterium tuberculosis/chemistry ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/enzymology ; Mycobacterium tuberculosis/genetics ; Sulfurtransferases/antagonists & inhibitors ; Sulfurtransferases/chemistry ; Sulfurtransferases/genetics ; Sulfurtransferases/metabolism ; Thiazolidines/chemical synthesis ; Thiazolidines/chemistry ; Thiazolidines/pharmacology ; Tuberculosis/drug therapy ; Tuberculosis/microbiology
    Chemical Substances Antitubercular Agents ; Bacterial Proteins ; Biological Products ; Caproates ; Thiazolidines ; Biotin (6SO6U10H04) ; Sulfurtransferases (EC 2.8.1.-) ; biotin synthetase (EC 2.8.1.6) ; mycobacidin (UX05P33K8J)
    Language English
    Publishing date 2019-02-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 2373-8227
    ISSN (online) 2373-8227
    DOI 10.1021/acsinfecdis.8b00345
    Database MEDical Literature Analysis and Retrieval System OnLINE

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