Bacterial moonlighting proteins and their role in virulence: A review

Bacterial moonlighting proteins are multifunctional molecules that perform distinct physiological roles beyond their classical enzymatic or structural functions. These proteins challenge the traditional “one gene, one protein, one function” paradigm by exhibiting multiple, unrelated activities dependent on factors such as sub cellular localization, environmental cues, and protein interactions. Predominantly found among Glycolytic enzymes, metabolic enzymes, and molecular chaperones, bacterial moonlighting proteins contribute significantly to virulence by mediating adhesion, immune modulation, tissue invasion, and biofilm formation. Surface localization enables these proteins to bind host extracellular matrix components like fibronectin and plasminogen, facilitating colonization and penetration of host tissues. Additionally, they modulate host immune responses to promote bacterial persistence. Despite their conserved metabolic roles, these proteins possess structural and regulatory plasticity allowing functional switching in response to environmental stimuli. Their central involvement in bacterial pathogenicity positions them as promising targets for novel antimicrobial therapies. However, challenges such as functional diversity across species, homology with host proteins, and bacterial compensatory mechanisms complicate therapeutic development. A deeper understanding of the molecular mechanisms, regulation, and structural features of bacterial moonlighting proteins is essential to exploit their vulnerabilities effectively, offering potential pathways for innovative treatments against antibiotic-resistant infections.