Following the Central Dogma: A Review of Fluoroquinolone Resistance Mechanisms in Aquatic Pathogenic Bacteria

Fluoroquinolone resistance in aquatic bacterial pathogens is a growing concern in aquaculture worldwide. Multidrug-resistant isolates are increasingly reported across major farming regions, and the potential transmission of resistance genes to humans through the food chain and environmental exposure has attracted attention beyond aquaculture. Most existing reviews discuss individual resistance mechanisms, such as target-site mutations, plasmid-mediated quinolone resistance (PMQR), efflux pumps, and altered membrane permeability, as discrete topics, with limited consideration of their interrelationships. This review takes a different approach. Using the central dogma of molecular biology as an organizing framework, it organizes fluoroquinolone resistance into four interconnected levels: gene, transcription, protein, and phenotype. Gene-level resistance involves point mutations in the quinolone resistance-determining region (QRDR) and the acquisition of PMQR genes. Transcriptional responses include coordinated upregulation of efflux pumps and downregulation of porins, which together reduce intracellular drug accumulation. Protein-level mechanisms include altered drug targets, target protection by Qnr proteins, drug efflux, and enzymatic modification of the drug. At the phenotypic level, PMQR-mediated low-level resistance provides a survival window during which subsequent QRDR mutations accumulate, whereas efflux pump overexpression confers higher-level resistance. Biofilm formation and metabolic reprogramming further stabilize the resistance phenotype at the population level. This framework highlights how resistance mechanisms interact across different molecular and cellular levels, rather than functioning independently or following a strictly linear sequence. Key gaps remain in understanding the regulatory roles of non-coding RNAs, the structural biology of PMQR proteins, and the use of multi-omics approaches to clarify regulation across these levels. Further research is needed to address these gaps.