Abstract
Farnesyltransferase inhibitors (FTIs) are focus for the treatment of several diseases, particularly in the field of cancer therapy. Their potential, however, goes even further, as a number of studies have evaluated FTIs for the treatment of infectious diseases such as malaria, African sleeping sickness, leishmaniosis, and hepatitis D virus infection. Little is known about protein prenylation mechanisms in human pathogens. However, disruption of IspA, a gene encoding the geranyltranstransferase of Staphylococcus aureus (S. aureus) leads to reprogramming of cellular behavior as well as impaired growth and decreased resistance to cell wall-targeting antibiotics. We used an agar well diffusion assay and a time kill assay and determined the minimum inhibitory concentrations of the FTIs lonafarnib and tipifarnib. Additionally, we conducted cell viability assays. We aimed to characterize the effect of these FTIs on S. aureus, methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis (S. epidermidis), Escherichia coli (E. coli), Enterococcus faecium (E. faecium), Klebsiella pneumoniae (K. pneumoniae), Pseudomonas aeruginosa (P. aeruginosa), and Streptococcus pneumoniae (S. pneumoniae). Both the FTIs lonafarnib and tipifarnib were capable of inhibiting the growth of the Gram-positive bacteria S. aureus, MRSA, S. epidermidis, and S. pneumoniae, whereas no effect was observed on Gram-negative bacteria. The analysis of the impact of lonafarnib and tipifarnib on common human pathogens might lead to novel insights into their defense mechanisms and therefore provide new therapeutic targets for antibiotic-resistant bacterial infections.
Highlights
In eukaryotic cells, several proteins are converted into functional proteins by posttranslational modifications (PTMs) (Lane and Beese, 2006)
Generation sequencing (NGS) analysis of S. aureus cells treated with both farnesyltransferase inhibitor (FTI) were conducted
Raw data were generated for S. aureus treated with lonafarnib (500 μM), tipifarnib (500 μM), and dimethyl sulfoxide (DMSO) for 6 h
Summary
Several proteins are converted into functional proteins by posttranslational modifications (PTMs) (Lane and Beese, 2006). These proteins are required for cell growth, differentiation, and apoptosis or general signaling pathway activity. One important PTM is prenylation, which is the covalent attachment of an isoprenoid residue to cysteine residues of Abbreviations: DMSO, dimethyl sulfoxide; FTI, farnesyltransferase inhibitor; MRSA, methicillin-resistant Staphylococcus aureus; CSB, casein/soy peptone broth; CSA, casein/soy peptone agar. The use of farnesyltransferase inhibitors (FTIs) to disrupt the functionality of the oncogene Ras, e.g., appears to be a promising therapeutic approach. The two FTIs tipifarnib and lonafarnib (Norman, 2002; Equbal et al, 2008) play an important role in the therapy of some diseases, such as progeria and cancer as well as in pathogen-based diseases, such as hepatitis D (Lane and Beese, 2006; Capell et al, 2008; Koh et al, 2015; Caviglia and Rizzetto, 2020); the only approved FTI is lonafarnib, which was approved for the treatment of Hutchinson–Gilford progeria syndrome in 2020 (U.S Food and Drug Administration, 2020)
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