Cinchonidine enhances intracellular erythromycin activity against Rhodococcus equi.

Area of Science:

• Microbiology
• Pharmacology
• Infectious Diseases

Background:

• Rhodococcus equi causes severe infections in foals and immunocompromised individuals.
• Intracellular survival of R. equi leads to multidrug resistance and treatment challenges.
• Novel therapeutic strategies are crucial for combating R. equi infections.

Purpose of the Study:

• To identify novel antibacterial compounds targeting R. equi.
• To evaluate the efficacy of natural compounds and their combinations against R. equi.
• To investigate the mechanism of action for synergistic antibacterial effects.

Main Methods:

• Screening of 3251 natural compounds against R. equi strains.
• Determination of minimal inhibitory concentrations and synergy using checkerboard assays.
• Assessment of intracellular efficacy in murine macrophages and redox stress quantification.

Main Results:

• Thirty-eight compounds selectively inhibited an mrx-deficient R. equi mutant, indicating redox-mediated mechanisms.
• Erythromycin (ERY) and cinchonidine (CIN) combination demonstrated significant synergy, reducing intracellular bacterial load.
• ERY-CIN synergy was linked to elevated oxidative stress, confirming a redox-based mechanism.

Conclusions:

• Cinchonidine (CIN) acts as a redox-active adjuvant, potentiating erythromycin's (ERY) intracellular activity against R. equi.
• The ERY-CIN combination targets bacterial redox homeostasis, enhancing clearance of intracellular R. equi.
• This combinatorial approach offers a promising strategy against multidrug-resistant intracellular pathogens.