Prodrug florfenicol amine is activated by intrinsic resistance to target Mycobacterium abscessus.
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Phelps Gregory A, Kurt Sinem, Jenner Alexander R, Anderson Shelby M, Jayasinghe Thalina D, Griffith Elizabeth C, Thompson Carl W, Yang Lei, Wicki Basil, Bright Frederick K, Loudon Victoria, Wright William C, Srivastava Ashish, Singh Amarinder, Thalluri Bhargavi, Park Hyunseo, Lee Robin B, Wright Anna K, Grant-Chapman Oliver, Conner Daryl K, Troyer Brennen T, Iverson Amy, Ochoado Jason, Pagala Vishwajeeth R, Wu Long, Byrum Stephanie, Fu Yingxue, Yuan Zu-Fei, High Anthony A, Schulthess Bettina, Rosch Jason W, Geeleher Paul, Hobbie Sven N, Boeck Lucas, Meibohm Bernd, Obregon-Henao Andres, Sander Peter, Lee Richard E
Аннотация
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.