2. Academic Validation
  3. Prodrug florfenicol amine is activated by intrinsic resistance to target Mycobacterium abscessus

Prodrug florfenicol amine is activated by intrinsic resistance to target Mycobacterium abscessus

  • Nat Microbiol. 2025 Nov;10(11):2875-2891. doi: 10.1038/s41564-025-02147-9.
Gregory A Phelps # 1 2,  Sinem Kurt # 3,  Alexander R Jenner 1 4,  Shelby M Anderson 1,  Thalina D Jayasinghe 1,  Elizabeth C Griffith 1,  Carl W Thompson 1,  Lei Yang 1,  Basil Wicki 5,  Frederick K Bright 5,  Victoria Loudon 1,  William C Wright 6,  Ashish Srivastava 4,  Amarinder Singh 4,  Bhargavi Thalluri 4,  Hyunseo Park 4,  Robin B Lee 1,  Anna K Wright 1,  Oliver Grant-Chapman 2,  Daryl K Conner 7,  Brennen T Troyer 7,  Amy Iverson 8,  Jason Ochoado 1,  Vishwajeeth R Pagala 9,  Long Wu 9,  Stephanie Byrum 9,  Yingxue Fu 9,  Zu-Fei Yuan 9,  Anthony A High 9,  Bettina Schulthess 3 10,  Jason W Rosch 8,  Paul Geeleher 6,  Sven N Hobbie 11,  Lucas Boeck 5 12,  Bernd Meibohm 4,  Andres Obregon-Henao 7,  Peter Sander 13 14,  Richard E Lee 15
Affiliations

Affiliations

  • 1 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 2 Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 3 Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland.
  • 4 Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA.
  • 5 Department of Biomedicine, University of Basel, Basel, Switzerland.
  • 6 Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 7 NTM Center, Mycobacteria Research Laboratory, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, USA.
  • 8 Department of Host-Microbe Interactions, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 9 Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 10 National Reference Center for Mycobacteria, Zurich, Switzerland.
  • 11 Division of Clinical Bacteriology and Mycology, University Hospital Basel, Basel, Switzerland.
  • 12 Pulmonary Medicine, University Hospital Basel, Basel, Switzerland.
  • 13 Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland. [email protected].
  • 14 National Reference Center for Mycobacteria, Zurich, Switzerland. [email protected].
  • 15 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA. [email protected].
  • # Contributed equally.
PMID: 41168430 DOI: 10.1038/s41564-025-02147-9
Abstract

Non-tuberculous mycobacteria are emerging pathogens with high intrinsic drug resistance. Among these, Mycobacterium abscessus is particularly refractory owing to its extensive array of resistance mechanisms. Here we introduce florfenicol amine (FF-NH2), a major metabolite of the Antibiotic florfenicol, which acts as a prodrug with narrow-spectrum activity against M. abscessus-chelonae complex species. FF-NH2 leverages intrinsic M. abscessus resistance conferred by the transcription factor WhiB7. It avoids WhiB7-dependent resistance mediated by the O-acetyltransferase Cat and is activated by the WhiB7-dependent N-acetyltransferase Eis2 in a prodrug fashion to generate the active translational inhibitor FF acetyl (FF-ac). FF-NH2 induces Eis2 expression through WhiB7, creating a feed-forward bioactivation loop, which increases FF-ac accumulation and antimicrobial action. FF-NH2 displays antiresistance properties, can synergize with Other Antibiotics and mitigates toxicity linked to mammalian mitochondrial ribosome inhibition. Importantly, FF-NH2 demonstrated efficacy in a murine model of M. abscessus Infection. These findings suggest intrinsic resistance can be exploited to develop safer and more effective treatments for this pathogen.

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