We are rapidly returning to a world in which bacterial infections are a major health issue. Pathogenic bacteria are able to colonize and cause pathology due to the possession of virulence factors such as adhesins, invasins, evasins and toxins. These are generally specifically evolved proteins with selective actions. It is, therefore, surprising that most human bacterial pathogens employ moonlighting proteins as virulence factors. Currently, >90 bacterial species employ one or more moonlighting protein families to aid colonization and induce disease. These organisms employ 90 moonlighting bacterial protein families and these include enzymes of the glycolytic pathway, tricarboxylic acid (TCA) cycle, hexosemonophosphate shunt, glyoxylate cycle and a range of other metabolic enzymes, proteases, transporters and, also, molecular chaperones and protein-folding catalysts. These proteins have homologues in eukaryotes and only a proportion of the moonlighting proteins employed are solely bacterial in origin. Bacterial moonlighting proteins can be divided into those with single moonlighting functions and those with multiple additional biological actions. These proteins contribute significantly to the population of virulence factors employed by bacteria and some are obvious therapeutic targets. Where examined, bacterial moonlighting proteins bind to target ligands with high affinity. A major puzzle is the evolutionary mechanism(s) responsible for bacterial protein moonlighting and a growing number of highly homologous bacterial moonlighting proteins exhibit widely different moonlighting actions, suggesting a lack in our understanding of the mechanism of evolution of protein active sites.

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