Fluoroquinolones as the linchpin of tuberculosis therapy: contrasting efficacy and resistance profiles in Mycobacterium tuberculosis versus Mycobacterium abscessus.

INTRODUCTION: Fluoroquinolones (FQs) are pharmacological cornerstone agents in global tuberculosis (TB) management, critical for both accelerating drug-sensitive regimens and defining the resistance spectrum of multidrug-resistant TB.

METHODS & RESULTS: To evaluate the therapeutic potential of this class across the mycobacterial spectrum, we conducted a comprehensive phenotypic screening campaign utilizing OTAVA and ECBD pilot-libraries against reference strains of Mycobacterium tuberculosis (Mtb) and Mycobacterium abscessus (Mab). This initial screen, followed by detailed bactericidal concentration (BC) and cytotoxicity assessments, identified and selected potent FQ derivatives for in-depth characterization. These FQ compounds exhibited exceptionally high potency against Mtb, with several demonstrating robust bactericidal activity at concentrations far below toxic levels to mammalian cells. This activity was retained in clinically relevant, challenging states, as the compounds effectively eliminated Mtb residing within human macrophages and persisted within protective biofilm structures. In stark contrast, Mab displayed marked intrinsic resistance. Most FQ derivatives highly potent against Mtb required significantly higher concentrations for inhibition and bactericidal effect against Mab. For instance, a leading clinical FQ showed substantially diminished activity against Mab compared to Mtb. Analysis of acquired resistance mechanisms demonstrated that both Mtb and Mab primarily rely on similar acquired point mutations in the Quinolone Resistance Determining Regions (QRDRs) of the gyrA and gyrB genes. However, molecular docking indicated a slight but significant reduction in theoretical binding affinity to the Mab gyrase complex.

DISCUSSION: We hypothesize that the profound differential in intrinsic susceptibility is at least partially driven by non-target factors. This work supports the continued critical role of FQs in Mtb therapy while highlighting the importance of structural modifications that could address hypothesized intrinsic resistance mechanisms in Mab.