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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Broad-Spectrum In Vitro Activity of Nα-Aroyl-N-Aryl-Phenylalanine Amides against Non-Tuberculous Mycobacteria and Comparative Analysis of RNA Polymerases

Antibiotics (2024)

Markus Lang Uday S. Ganapathy Rana Abdelaziz Thomas Dick Adrian Richter

This study investigates the in vitro activity of Nα-aroyl-N-aryl-phenylalanine amides (AAPs), previously identified as antimycobacterial RNA polymerase (RNAP) inhibitors, against a panel of 25 non-tuberculous mycobacteria (NTM). The compounds, including the hit compound MMV688845, were selected based on their structural diversity and previously described activity against mycobacteria. Bacterial strains, including the M. abscessus complex, M. avium complex, and other clinically relevant NTM, were cultured and subjected to growth inhibition assays. The results demonstrate significant activity against the most common NTM pathogens from the M. abscessus and M. avium complexes. Variations in activity were observed against other NTM species, with for instance M. ulcerans displaying high susceptibility and M. xenopi and M. simiae resistance to AAPs. Comparative analysis of RNAP β and β′ subunits across mycobacterial species revealed strain-specific polymorphisms, providing insights into differential compound susceptibility. While conservation of target structures was observed, differences in compound activity suggested influences beyond drug–target interactions. This study highlights the potential of AAPs as effective antimycobacterial agents and emphasizes the complex interplay between compound structure, bacterial genetics, and in vitro activity.

Antimycobacterial

Mycobacterium abscessus

Mycobacterium avium complex

10.3390/antibiotics13050404

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Activity of Oral Tebipenem-Avibactam in a Mouse Model of Mycobacterium abscessus Lung Infection

Antimicrobial Agents and Chemotherapy (2023)

Dereje A. Negatu Rubén González del Río Mónica Cacho David Barros-Aguirre Joël Lelièvre

The combination of the β-lactam tebipenem and the β-lactamase inhibitor avibactam shows potent bactericidal activity against Mycobacterium abscessus in vitro. Here, we report that the combination of the respective oral prodrugs tebipenem-pivoxil and avibactam ARX-1796 showed efficacy in a mouse model of M. abscessus lung infection. The results suggest that tebipenem-avibactam presents an attractive oral drug candidate pair for the treatment of M. abscessus pulmonary disease and could inform the design of clinical trials.

Mycobacterium abscessus

Avibactam

Antimycobacterial

10.1128/aac.01459-22

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Citations (12)

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

The study of the bacterial periplasm requires techniques with sufficient spatial resolution and sensitivity to resolve the components and processes within this subcellular compartment. Peroxidase-mediated biotinylation has enabled targeted labeling of proteins within subcellular compartments of mammalian cells. We investigated whether this methodology could be applied to the bacterial periplasm. In this study, we demonstrated that peroxidase-mediated biotinylation can be performed in mycobacteria and Escherichia coli. To eliminate detection artifacts from natively biotinylated mycobacterial proteins, we validated two alternative labeling substrates, tyramide azide and tyramide alkyne, which enable biotin-independent detection of labeled proteins. We also targeted peroxidase expression to the periplasm, resulting in compartment-specific labeling of periplasmic versus cytoplasmic proteins in mycobacteria. Finally, we showed that this method can be used to validate protein relocalization to the cytoplasm upon removal of a secretion signal. This novel application of peroxidase-mediated protein labeling will advance efforts to characterize the role of the periplasm in bacterial physiology and pathogenesis.

Compartment (ship)

10.1021/acsinfecdis.8b00044

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In Vitro Profiling of the Synthetic RNA Polymerase Inhibitor MMV688845 against Mycobacterium abscessus

Microbiology Spectrum (2022)

Lea Mann Uday S. Ganapathy Rana Abdelaziz Markus Lang Matthew D. Zimmerman

In a library screen of tuberculosis-active compounds for anti-Mycobacterium abscessus activity, we previously identified the synthetic phenylalanine amide MMV688845. In Mycobacterium tuberculosis, this class was shown to target the RpoB subunit of RNA polymerase, engaging a binding site distinct from that of the rifamycins. Due to its bactericidal activity, rifampicin is a key drug for the treatment of tuberculosis (TB). However, this natural product shows poor potency against M. abscessus due to enzymatic modification, and its clinical use is limited. Here, we carried out in vitro microbiological profiling of MMV688845 to determine its attractiveness as a substrate for a chemistry optimization project. MMV688845 was broadly active against the M. abscessus complex, displayed bactericidal against M. abscessus in vitro, and in a macrophage infection model showed additivity with commonly used anti-M. abscessus antibiotics and synergy with macrolides. Analyses of spontaneous resistant mutants mapped resistance to RpoB, confirming that MMV688845 has retained its target in M. abscessus. Together with its chemical tractability, the presented microbiological profiling reveals MMV688845 as an attractive starting point for hit-to-lead development to improve potency and to identify a lead compound with demonstrated oral in vivo efficacy. IMPORTANCE Infections with nontuberculous mycobacteria are an increasing health problem, and only a few new drug classes show activity against these multidrug-resistant bacteria. Due to insufficient therapy options, the development of new drug leads is necessary and should be advanced. The lead compound MMV688845, a substance active against M. abscessus complex, was characterized in depth. In various assays, it showed activity against M. abscessus, synergy with other antibiotics, and bactericidal effects.

Mycobacterium abscessus

rpoB

Nontuberculous Mycobacteria

10.1128/spectrum.02760-22

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Two enzymes with redundant fructose bisphosphatase activity sustain gluconeogenesis and virulence in Mycobacterium tuberculosis

Nature Communications (2015)

Uday S. Ganapathy Joeli Marrero Susannah F. Calhoun Hyungjin Eoh Luiz Pedro S. de Carvalho

Abstract The human pathogen Mycobacterium tuberculosis ( Mtb ) likely utilizes host fatty acids as a carbon source during infection. Gluconeogenesis is essential for the conversion of fatty acids into biomass. A rate-limiting step in gluconeogenesis is the conversion of fructose 1,6-bisphosphate to fructose 6-phosphate by a fructose bisphosphatase (FBPase). The Mtb genome contains only one annotated FBPase gene, glpX . Here we show that, unexpectedly, an Mtb mutant lacking GLPX grows on gluconeogenic carbon sources and has detectable FBPase activity. We demonstrate that the Mtb genome encodes an alternative FBPase (GPM2, Rv3214) that can maintain gluconeogenesis in the absence of GLPX. Consequently, deletion of both GLPX and GPM2 is required for disruption of gluconeogenesis and attenuation of Mtb in a mouse model of infection. Our work affirms a role for gluconeogenesis in Mtb virulence and reveals previously unidentified metabolic redundancy at the FBPase-catalysed reaction step of the pathway.

Gluconeogenesis

Fructose 1,6-bisphosphatase

10.1038/ncomms8912

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Citations (63)

Repositioning rifamycins for Mycobacterium abscessus lung disease

Expert Opinion on Drug Discovery (2019)

Uday S. Ganapathy Véronique Dartois Thomas Dick

Introduction: The treatment of Mycobacterium abscessus lung disease faces significant challenges due to intrinsic antibiotic resistance. New drugs are needed to cure this incurable disease. The key anti-tubercular rifamycin, rifampicin, suffers from low potency against M. abscessus and is not used clinically. Recently, another member of the rifamycin class, rifabutin, was shown to be active against the opportunistic pathogen.Areas covered: In this review, the authors discuss the rifamycins as a reemerging drug class for treating M. abscessus infections. The authors focus on the differential potency of rifampicin and rifabutin against M. abscessus in the context of intrinsic antibiotic resistance and bacterial uptake and metabolism. Reports of rifamycin-based drug synergies and rifamycin potentiation by host-directed therapy are evaluated.Expert opinion: While repurposing rifabutin for M. abscessus lung disease may provide some immediate relief, the repositioning (chemical optimization) of rifamycins offers long-term potential for improving clinical outcomes. Repositioning will require a multifaceted approach involving renewed screening of rifamycin libraries, medicinal chemistry to improve ‘bacterial cell pharmacokinetics’, better models of bacterial pathophysiology and infection, and harnessing of drug synergies and host-directed therapy towards the development of a better drug regimen.

Rifabutin

Rifamycin

Mycobacterium abscessus

10.1080/17460441.2019.1629414

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Citations (54)

CCDC 2231847: 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.cc2dxf2v

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A Mycobacterium tuberculosis NBTI DNA Gyrase Inhibitor Is Active against Mycobacterium abscessus

Antimicrobial Agents and Chemotherapy (2021)

Uday S. Ganapathy Rubén González del Río Mónica Cacho-Izquierdo Fátima Ortega Joël Lelièvre

Fluoroquinolones—the only clinically used DNA gyrase inhibitors—are effective against tuberculosis (TB) but are in limited clinical use for nontuberculous mycobacteria (NTM) lung infections due to intrinsic drug resistance. We sought to test alternative DNA gyrase inhibitors for anti-NTM activity. Mycobacterium tuberculosis Gyrase Inhibitors (MGIs), a subclass of Novel Bacterial Topoisomerase Inhibitors (NBTIs), were recently shown to be active against the tubercle bacillus.

Mycobacterium abscessus

Nontuberculous Mycobacteria

Topoisomerase IV

10.1128/aac.01514-21

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Citations (19)

A Leucyl-tRNA Synthetase Inhibitor with Broad-Spectrum Antimycobacterial Activity

Antimicrobial Agents and Chemotherapy (2021)

Uday S. Ganapathy Rubén González del Río Mónica Cacho-Izquierdo Fátima Ortega Joël Lelièvre

Global infections by non-tuberculous mycobacteria (NTM) are steadily rising. New drugs are needed to treat NTM infections, but the NTM drug pipeline remains poorly populated and focused on repurposing or reformulating approved antibiotics. We sought to accelerate

Antimycobacterial

Nontuberculous Mycobacteria

Repurposing

Broad spectrum

Mycobacterium avium complex

10.1128/aac.02420-20

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Citations (29)

CCDC 2231845: Experimental Crystal Structure Determination

The Cambridge Structural Database (2023)

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

10.5517/ccdc.csd.cc2dxf0s

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