Virulence alterations in staphylococcus aureus upon treatment with the sub-inhibitory concentrations of antibiotics

The treatment of patients with Staphylococcus aureus infections mainly relies on antistaphylococcal regimens that are established with effective antibiotics. In antibiotic therapy or while living in nature, pathogens often face the sub-inhibitory concentrations (sub-MICs) of antibiotics due to drug pharmacokinetics, diffusion barriers, waste emission, resistant organism formation, and farming application. Different categories of antibiotics at sub-MICs have diverse effects on the physiological and chemical properties of microorganisms. These effects can result in virulence alterations. However, the mechanisms underlying the actions of antibiotics at sub-MICs on S. aureus virulence are obscure. In this review, we focus on the effects of sub-MICs of antibiotics on S. aureus virulence from the aspects of cell morphological change, virulence factor expression, bacterial adherence and invasion, staphylococcal biofilm formation, and small-colony variant (SCV) production. The possible mechanisms of antibiotic-induced S. aureus virulence alterations are also addressed. Five main aspects of bacterial virulence can be changed in S. aureus exposure to the sub-MIC levels of antibiotics, resulting in deformed bacterial cells to stimulate abnormal host immune responses, abnormally expressed virulence factors to alter disease development, changed bacterial adhesion and invasion abilities to affect colonization and diffusion, altered biofilm formation to potentate material-related infections, and increased SCV formation to achieve persistent infection and recurrence. These advanced findings expand our knowledge to rethink the molecular signaling roles of antibiotics beyond their actions as antimicrobial agents.