Therapeutic potential of spiro compounds against Staphylococcus aureus: a comprehensive review

Staphylococcus aureus is a highly virulent Gram-positive pathogen implicated in a wide spectrum of severe infections, including pneumonia, endocarditis, osteomyelitis, and bacteremia. In 2024, the World Health Organization (WHO) designated S. aureus as a high-burden, drug-resistant bacterial pathogen of global priority, reinforcing the urgent need for innovative antibacterial strategies. Spirocyclic scaffolds, defined by their rigid three-dimensional architectures and diverse pharmacological properties, have emerged as versatile and privileged frameworks in medicinal chemistry. In this review, we provide a comprehensive account of natural and synthetic spirocyclic derivatives active against S. aureus, with an in-depth discussion of their structural diversity, structure-activity relationships (SARs), and classification into distinct spirocyclic categories. Particular emphasis is placed on the molecular targets modulated by these scaffolds, highlighting their mechanistic relevance in combating S. aureus infections. The therapeutic significance of FDA-approved spiro-based drugs is also discussed in the context of antibacterial drug discovery. By consolidating recent advances, mechanistic insights, and SAR trends, this review aims to guide the rational design and development of next-generation spirocyclic antibacterials with enhanced potency, selectivity, and safety profiles.