Antimicrobial Resistance in Rhodococcus equi and the Promise of Synergistic Therapies.

Rhodococcus equi is an opportunistic intracellular pathogen responsible for severe pneumonia in foals and has emerged as an important cause of infection in immunocompromised humans. The treatment of R. equi infections in foals relies mainly on the combination of macrolides and rifampin. However, the increasing incidence of multidrug-resistant (MDR) isolates has raised significant therapeutic challenges. The mechanisms underlying this resistance include mutations in target genes, activation of efflux pumps, and biofilm formation, which collectively compromise the efficacy of conventional antibiotics. Recently, growing concern over antibiotic failure has accelerated research into alternative and synergistic strategies to enhance antibacterial efficacy and reduce the development of resistance. Natural and synthetic compounds, as well as optimized antibiotic combinations, have shown promising synergistic effects by enhancing intracellular accumulation, disrupting redox homeostasis, or inhibiting efflux systems. Experimental models employing checkerboard and time-kill assays, as well as redox-sensitive biosensors, have demonstrated that certain antibiotic combinations can influence bacterial susceptibility to antibiotic exposure. Furthermore, integrating molecular tools provides valuable insight into bacterial responses to oxidative and antibiotic stress, paving the way for novel therapeutic designs. This review summarizes the current understanding of the molecular factors contributing to antimicrobial resistance in R. equi and assesses new therapeutic approaches aimed at overcoming these challenges. It highlights recent findings on strategies to improve treatment outcomes and manage antimicrobial resistance.