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

## TL;DR

A new antibiotic called florfenicol amine exploits Mycobacterium abscessus's own resistance mechanisms to fight infection.

## Contribution

Florfenicol amine is a novel prodrug that uses intrinsic resistance mechanisms in M. abscessus to activate its antibacterial effect.

## Key findings

- Florfenicol amine is activated by the N-acetyltransferase Eis2 in a prodrug fashion to form FF acetyl.
- Florfenicol amine induces Eis2 expression through the transcription factor WhiB7, creating a feed-forward activation loop.
- Florfenicol amine showed efficacy in a murine model of M. abscessus infection and can synergize with other antibiotics.

## 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.

Florfenicol amine hijacks intrinsic resistance in Mycobacterium abscessus, highlighting that antimicrobial resistance mechanisms can be harnessed for antibiotic activation.