Uday S. Ganapathy

Hackensack Meridian Health

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Thomas Dick

Georgetown University Medical Center

Véronique Dartois

Hackensack Meridian Health

Adrian Richter

Martin Luther University Halle-Wittenberg

Martin Gengenbacher

Center for Discovery

Markus Lang

Martin Luther University Halle-Wittenberg

Rana Abdelaziz

Martin Luther University Halle-Wittenberg

Matthew Zimmerman

Center for Discovery

Rüdiger W. Seidel

Martin Luther University Halle-Wittenberg

Richard Goddard

Max-Planck-Institut für Kohlenforschung

Lea Mann

Martin Luther University Halle-Wittenberg

Cooperative Institutions

Hackensack Meridian Health

Center for Discovery

Rutgers, The State University of New Jersey

Martin Luther University Halle-Wittenberg

GlaxoSmithKline (Spain)

Rutgers New Jersey Medical School

Stony Brook University

National University of Singapore

Cornell University

University of Minnesota

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TBAJ-876, a 3,5-Dialkoxypyridine Analogue of Bedaquiline, Is Active against Mycobacterium abscessus

Antimicrobial Agents and Chemotherapy (2020)

Jickky Palmae Sarathy Uday S. Ganapathy Matthew D. Zimmerman Véronique Dartois Martin Gengenbacher

Lung disease caused by Mycobacterium abscessus is very difficult to cure, and treatment failure rates are high. The antituberculosis drug bedaquiline (BDQ) is used as salvage therapy against this dreadful disease. However, BDQ is highly lipophilic, displays a long terminal half-life, and presents a cardiotoxicity liability associated with QT interval prolongation. Recent medicinal chemistry campaigns resulted in the discovery of 3,5-dialkoxypyridine analogues of BDQ which are less lipophilic, have higher clearance, and display lower cardiotoxic potential. TBAJ-876, a clinical development candidate of this series, shows attractive in vitro antitubercular activity and efficacy in a murine tuberculosis model. Here, we asked whether TBAJ-876 is active against M. abscessus TBAJ-876 displayed submicromolar in vitro activity against reference strains representing the three subspecies of M. abscessus and against a collection of clinical isolates. Drug-drug potency interaction studies with commonly used anti-M. abscessus antibiotics showed no antagonistic effects, suggesting that TBAJ-876 could be coadministered with currently used drugs. Efficacy studies, employing a mouse model of M. abscessus infection, demonstrated potent activity in vivo In summary, we demonstrate that TBAJ-876 shows attractive in vitro and in vivo activities against M. abscessus, similar to its BDQ parent. This suggests that next-generation BDQ, with improved tolerability and pharmacological profiles, may be useful for the treatment of M. abscessus lung disease in addition to the treatment of tuberculosis.

Bedaquiline

Mycobacterium abscessus

10.1128/aac.02404-19

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Citations (44)

Correction to Compartment-Specific Labeling of Bacterial Periplasmic Proteins by Peroxidase-Mediated Biotinylation

ACS Infectious Diseases (2018)

Uday S. Ganapathy Lu Bai Linpeng Wei Kathryn A. Eckartt Clarissa M. Lett

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to Compartment-Specific Labeling of Bacterial Periplasmic Proteins by Peroxidase-Mediated BiotinylationUday S. GanapathyUday S. GanapathyMore by Uday S. Ganapathy, Lu BaiLu BaiMore by Lu Bai, Linpeng WeiLinpeng WeiMore by Linpeng Weihttp://orcid.org/0000-0003-3257-7691, Kathryn A. EckarttKathryn A. EckarttMore by Kathryn A. Eckartt, Clarissa M. LettClarissa M. LettMore by Clarissa M. Lett, Mary L. PrevitiMary L. PrevitiMore by Mary L. Previti, Isaac S. CarricoIsaac S. CarricoMore by Isaac S. Carrico, and Jessica C. Seeliger*Jessica C. SeeligerMore by Jessica C. Seeligerhttp://orcid.org/0000-0001-7148-1073Cite this: ACS Infect. Dis. 2018, 4, 7, 1157Publication Date (Web):June 25, 2018Publication History Received18 June 2018Published online25 June 2018Published inissue 13 July 2018https://pubs.acs.org/doi/10.1021/acsinfecdis.8b00143https://doi.org/10.1021/acsinfecdis.8b00143correctionACS PublicationsCopyright © 2018 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views887Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (214 KB) Get e-Alertsclose Get e-Alerts

Compartment (ship)

10.1021/acsinfecdis.8b00143

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Redesign of Rifamycin Antibiotics to Overcome ADP‐Ribosylation‐Mediated Resistance

Angewandte Chemie International Edition (2022)

Tian Lan Uday S. Ganapathy Sachin Sharma Yong‐Mo Ahn Matthew Zimmerman

Rifamycin antibiotics are a valuable class of antimicrobials for treating infections by mycobacteria and other persistent bacteria owing to their potent bactericidal activity against replicating and non-replicating pathogens. However, the clinical utility of rifamycins against Mycobacterium abscessus is seriously compromised by a novel resistance mechanism, namely, rifamycin inactivation by ADP-ribosylation. Using a structure-based approach, we rationally redesign rifamycins through strategic modification of the ansa-chain to block ADP-ribosylation while preserving on-target activity. Validated by a combination of biochemical, structural, and microbiological studies, the most potent analogs overcome ADP-ribosylation, restored their intrinsic low nanomolar activity and demonstrated significant in vivo antibacterial efficacy. Further optimization by tuning drug disposition properties afforded a preclinical candidate with remarkable potency and an outstanding pharmacokinetic profile.

Rifamycin

10.1002/anie.202211498

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Citations (14)

Gut Microbiota Metabolite Indole Propionic Acid Targets Tryptophan Biosynthesis in Mycobacterium tuberculosis

mBio (2019)

Dereje A. Negatu Y. Yamada Yu Xi Mei‐Lin Go Matthew Zimmerman

New drugs against tuberculosis are urgently needed. The tryptophan (Trp) analog indole propionic acid (IPA) is the first antitubercular metabolite produced by human gut bacteria. Here, we show that this antibiotic blocks Trp synthesis, an in vivo essential biosynthetic pathway in M. tuberculosis . Intriguingly, IPA acts by decoupling a bacterial feedback regulatory mechanism: it mimics Trp as allosteric inhibitor of anthranilate synthase, thereby switching off Trp synthesis regardless of intracellular Trp levels. The identification of IPA’s target paves the way for the discovery of more potent TrpE ligands employing rational, target-based lead optimization.

10.1128/mbio.02781-18

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Citations (69)

Synthesis and Characterization of Phenylalanine Amides Active against Mycobacterium abscessus and Other Mycobacteria

Journal of Medicinal Chemistry (2023)

Markus Lang Uday S. Ganapathy Lea Mann Rana Abdelaziz Rüdiger W. Seidel

Nα-2-thiophenoyl-d-phenylalanine-2-morpholinoanilide [MMV688845, Pathogen Box; Medicines for Malaria Venture; IUPAC: (2R)-N-(1-((2-morpholinophenyl)amino)-1-oxo-3-phenylpropan-2-yl)thiophene-2-carboxamide)] is a hit compound, which shows activity against Mycobacterium abscessus (MIC90 6.25–12.5 μM) and other mycobacteria. This work describes derivatization of MMV688845 by introducing a thiomorpholine moiety and the preparation of the corresponding sulfones and sulfoxides. The molecular structures of three analogs are confirmed by X-ray crystallography. Conservation of the essential R configuration during synthesis is proven by chiral HPLC for an exemplary compound. All analogs were characterized in a MIC assay against M. abscessus, Mycobacterium intracellulare, Mycobacterium smegmatis, and Mycobacterium tuberculosis. The sulfone derivatives exhibit lower MIC90 values (M. abscessus: 0.78 μM), and the sulfoxides show higher aqueous solubility than the hit compound. The most potent derivatives possess bactericidal activity (99% inactivation of M. abscessus at 12.5 μM), while they are not cytotoxic against mammalian cell lines.

Mycobacterium abscessus

Mycobacterium smegmatis

Moiety

Antimycobacterial

Nontuberculous Mycobacteria

10.1021/acs.jmedchem.3c00009

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Citations (12)

Why Matter Matters: Fast-Tracking Mycobacterium abscessus Drug Discovery

Molecules (2022)

Uday S. Ganapathy Thomas Dick

Unlike Tuberculosis (TB), Mycobacterium abscessus lung disease is a highly drug-resistant bacterial infection with no reliable treatment options. De novo M. abscessus drug discovery is urgently needed but is hampered by the bacterium’s extreme drug resistance profile, leaving the current drug pipeline underpopulated. One proposed strategy to accelerate de novo M. abscessus drug discovery is to prioritize screening of advanced TB-active compounds for anti-M. abscessus activity. This approach would take advantage of the greater chance of homologous drug targets between mycobacterial species, increasing hit rates. Furthermore, the screening of compound series with established structure–activity-relationship, pharmacokinetic, and tolerability properties should fast-track the development of in vitro anti-M. abscessus hits into lead compounds with in vivo efficacy. In this review, we evaluated the effectiveness of this strategy by examining the literature. We found several examples where the screening of advanced TB chemical matter resulted in the identification of anti-M. abscessus compounds with in vivo proof-of-concept, effectively populating the M. abscessus drug pipeline with promising new candidates. These reports validate the screening of advanced TB chemical matter as an effective means of fast-tracking M. abscessus drug discovery.

Mycobacterium abscessus

Bedaquiline

Nontuberculous Mycobacteria

10.3390/molecules27206948

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Citations (12)

Blocking ADP-ribosylation expands the anti-mycobacterial spectrum of rifamycins

Microbiology Spectrum (2023)

Uday S. Ganapathy Tian Lan Véronique Dartois Courtney C. Aldrich Thomas Dick

The clinical utility of rifamycins against non-tuberculous mycobacterial (NTM) disease is limited by intrinsic drug resistance achieved by ADP-ribosyltransferase Arr. By blocking the site of ribosylation, we recently optimized a series of analogs with substantially improved potency against

Rifabutin

Rifamycin

Mycobacterium abscessus

Nontuberculous Mycobacteria

Mycobacterium fortuitum

10.1128/spectrum.01900-23

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Citations (5)

CCDC 2231846: Experimental Crystal Structure Determination

The Cambridge Structural Database (2023)

Markus Lang Uday S. Ganapathy Lea Mann Rana Abdelaziz Rüdiger W. Seidel

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

10.5517/ccdc.csd.cc2dxf1t

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Citations (0)

Redesign of Rifamycin Antibiotics to Overcome ADP‐Ribosylation‐Mediated Resistance

Angewandte Chemie (2022)

Tian Lan Uday S. Ganapathy Sachin Sharma Yong‐Mo Ahn Matthew D. Zimmerman

Abstract Rifamycin antibiotics are a valuable class of antimicrobials for treating infections by mycobacteria and other persistent bacteria owing to their potent bactericidal activity against replicating and non‐replicating pathogens. However, the clinical utility of rifamycins against Mycobacterium abscessus is seriously compromised by a novel resistance mechanism, namely, rifamycin inactivation by ADP‐ribosylation. Using a structure‐based approach, we rationally redesign rifamycins through strategic modification of the ansa ‐chain to block ADP‐ribosylation while preserving on‐target activity. Validated by a combination of biochemical, structural, and microbiological studies, the most potent analogs overcome ADP‐ribosylation, restored their intrinsic low nanomolar activity and demonstrated significant in vivo antibacterial efficacy. Further optimization by tuning drug disposition properties afforded a preclinical candidate with remarkable potency and an outstanding pharmacokinetic profile.

Rifamycin

10.1002/ange.202211498

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Citations (2)

ADP-ribosylation-resistant rifabutin analogs show improved bactericidal activity against drug-tolerant M. abscessus in caseum surrogate

Antimicrobial Agents and Chemotherapy (2023)

Min Xie Uday S. Ganapathy Tian Lan Paulina Osiecki Jansy P. Sarathy

Necrotic lesions and cavities filled with caseum are a hallmark of mycobacterial pulmonary disease. Bronchocavitary

Rifabutin

10.1128/aac.00381-23

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Citations (5)