Multimodal strategies overcome energy barrier for aminoglycoside uptake in S. aureus persisters

Persistent Staphylococcus aureus infections are a major therapeutic challenge due to metabolically dormant persister cells that survive antibiotic exposure without genetic resistance. Aminoglycosides, despite potent bactericidal activity, fail against these persisters because their uptake relies on an energy-dependent proton motive force (PMF). This critical bottleneck prevents effective treatment, leading to recurrent infections and therapeutic failures. Understanding and overcoming this energy-dependent barrier is crucial for developing effective strategies against recalcitrant S. aureus infections.

This review synthesizes emerging strategies designed to overcome the energy-dependent barrier to aminoglycoside uptake in metabolically dormant Staphylococcus aureus persister cells. It systematically examines three primary approaches: metabolic stimulation to reactivate membrane energetics, membrane-targeting adjuvants to bypass PMF for antibiotic entry, and rationally engineered aminoglycoside hybrids, such as peptide-conjugated variants, that achieve self-directed, energy-independent penetration. The review integrates findings from various studies to highlight the therapeutic potential of combinatorial regimens.

The review identifies three key multimodal strategies to sensitize Staphylococcus aureus persisters to aminoglycosides. First, metabolic stimulation using specific carbon sources or PMF-modulating agents effectively reactivates membrane energetics, thereby restoring aminoglycoside uptake in dormant cells. This approach leverages the persisters' dormant state by re-energizing their cellular machinery. Second, membrane-targeting adjuvants bypass the PMF requirement entirely, enabling antibiotic entry via biophysical remodeling and disruption of the lipid bilayer, providing a direct route for drug delivery. Third, rationally engineered aminoglycoside hybrids, specifically peptide-conjugated variants, achieve self-directed, energy-independent penetration while preserving their crucial ribosomal targeting mechanism. These variants offer a promising avenue for intrinsic bypass of the energy barrier. Collectively, these strategies demonstrate that aminoglycoside failure against S. aureus persisters is a modifiable physiological limitation, not intrinsic resistance.

The convergence of metabolic and membrane-based potentiation underscores the therapeutic potential of combinatorial regimens tailored to the unique bioenergetic state of persisters.