Genomic regulation of the diphtheria toxin gene and Its implications for molecular diagnostics and surveillance in low-resource settings.

Corynebacterium diphtheriae remains a significant, though often underestimated, public health concern, particularly in low- and middle-income countries. The pathogenicity of the disease is primarily determined by diphtheria toxin (DT), which is produced by the tox gene, a bacteriophage-associated element, and is tightly regulated by the iron-dependent transcriptional repressor DtxR, encoded by the dtxR gene. Despite extensive investigation into the molecular biology of DT, its regulation within the broader genomic organization, as well as its implications for diagnostic methods and surveillance strategies, have not yet been fully elucidated. This review consolidates existing evidence regarding the genomic context and molecular regulation of the tox gene, encompassing chromosomal organization, variability in GC content, genomic islands, and mechanisms of horizontal gene transfer. Significant attention is focused on lysogenic conversion mediated by corynephages and regulatory pathways responsive to iron. We also evaluate both established and novel molecular diagnostic approaches, including PCR, real-time PCR, sequencing technologies, and isothermal amplification methods like loop-mediated isothermal amplification (LAMP). Recent genomic discoveries, including pan-genome variation, CRISPR-Cas mechanisms, and the emergence of non-toxigenic tox-bearing strains are analyzed in relation to diagnostic precision and epidemiological surveillance. Understanding the genomic regulation and evolutionary dynamics of toxin production is essential for improving diagnostic accuracy and strengthening surveillance systems, particularly in resource-limited settings where diphtheria is often underdiagnosed and underreported.