Introduction
The emergence of antibiotic resistance is steadily increasing. One way to partially overcome these problems is to test already approved drugs (drug repurposing). Farnesyltransferase inhibitors (FTIs), primarily used in cancer therapy, have shown antimicrobial effects against some gram-positive bacteria [1]. To explore their impact on other gram-positive as well as gram-negative bacteria and assess potential synergy, FTIs are tested with colistin, which is known to disrupt the outer membrane. This study includes not only the key ESKAPE pathogen panel but also additional bacterial strains to gain a broad understanding of differential bacterial responses to FTIs. This approach aims to better understand and categorize FTIs" properties and identify dose-dependent synergistic effects relevant for the treatment of resistant bacteria.
Materials & Methods
Ten bacterial strains were tested to evaluate potential synergy between colistin and various drugs, focusing on FTIs and the ESKAPE panel. Antimicrobial susceptibilities were determined by broth microdilution. Synergy was assessed using a checkerboard assay to calculate ∑FIC values.
Results
When combined with sub-MIC colistin, FTIs inhibited the growth of gram-negative bacteria. Tipifarnib, an imidazole-containing heterocyclic FTI, demonstrated stronger effects on gram-negative bacteria than lonafarnib, a non-peptidic tricyclic FTI. Additionally, the peptidomimetic FTIs B581 and FTI-277 inhibited the growth of gram-negative bacteria in combination with colistin but showed no effect on the gram-positive strains tested. In contrast, bempedoic acid and αHFP, which both target the mevalonate pathway, exhibited no inhibitory activity.
Discussion
FTIs inhibited both gram-positive and gram-negative bacteria when combined with sub-MIC colistin, potentially reducing the required colistin dosage and thus minimizing side effects. This combination may also target colistin-resistant bacteria carrying the mcr-1 gene, the most prevalent and well-characterised colistin resistance gene. The mechanism of action likely differs from the eukaryotic pathway. The species-dependent effects suggest FTIs disrupt multiple biosynthetic pathways. Further studies will be conducted to clarify the mechanisms.
[1] Weber et al. 2019 Front. Microbiol. 12, 628283