Small molecule antipathogenic agents against Staphylococcus aureus infections

Staphylococcus aureus, a Gram-positive bacterium, is a pathogen capable of infecting nearly all host tissues, causing severe morbidity and mortality. Antibiotic resistant S. aureus are abundant, and multidrug resistant strains are emerging worldwide. The emergence and spread of antibiotic resistant bacterial strains is a growing public health concern, and new approaches are urgently needed to combat this threat. One promising strategy is to develop so-called ‘antipathogenic’ drugs, which acts by blocking bacterial virulence factors. S. aureus produces an array of virulence factors that enhance bacterium survival and spreading in the host by degrading host tissue, liberating nutrients from the host, and evading host immune responses. In contrast to antibiotics, antipathogenic drugs do not kill bacteria or stop their growth and are assumed not to impose a strong selection for resistance traits. Thus, by targeting virulence factors, it may be possible to reduce the severity of bacterial infections, giving the immune system an upper hand, without promoting the development of resistance. This review describes work done on developing small molecules that target three virulence categories: pore-forming toxins, immune evasion, and quorum sensing. We discuss the structure-activity relationships (SAR) of the various compounds investigated, focusing on their mechanisms of action and therapeutic potential. The review highlights the potential of targeting virulence factors as a promising strategy to combat antibiotic resistant infections, and suggests directions for further research to identify new compounds with improved efficacy.